subject:(Topoisomerase)

1. Antônio Claudio da Silva Lins. Estudo Químico e Atividade Antioxidante de Bauhinia Pentandra (Bong.) Vog. Ex Steud e Avaliação da Atividade Inibitória da Enzima Dna Topoisomerase II-a Humana de Substâncias Naturais e Semi-Sintéticas.

Degree: 2008, Universidade Federal da Paraíba

URL: http://bdtd.biblioteca.ufpb.br/tde_busca/arquivo.php?codArquivo=630 ; http://bdtd.biblioteca.ufpb.br/tde_busca/arquivo.php?codArquivo=631

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A espécie Bauhinia pentandra (Bong.) Vog. ex Steud (Leguminosae), conhecida como mororó com espinho é comum do Nordeste brasileiro. A enzima DNA topoisomerase II-α (topo… (more)

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A espécie Bauhinia pentandra (Bong.) Vog. ex Steud (Leguminosae), conhecida como mororó com espinho é comum do Nordeste brasileiro. A enzima DNA topoisomerase II-α (topo II) é responsável pelo relaxamento do DNA durante os processos de divisão celular e está envolvida em diversos tipos de câncer, sendo considerada um alvo potencial no tratamento desta doença. Este trabalho teve como objetivo estudar a composição química e atividade antioxidante das cascas das raízes de B. pentandra e a análise da atividade inibitória da topo II por compostos naturais e semi-sintéticos. O estudo químico da espécie vegetal resultou no isolamento do glicosídeo cianogênico litospermosida e de uma mistura dos esteróides β-sitosterol e estigmasterol. A litospermosida foi acetilada e as estruturas foram identificadas através de dados espectrométricos como IV e RMN1H e 13C, incluindo 2D. O extrato EtOH bruto e as frações hexânica, AcOEt, MeOH e a substância litospermosida foram submetidos aos testes antioxidantes (DPPH, ABTS, atividade quelatogênica do íon Fe2+). A determinação de fenólicos totais também foi realizada com o extrato e com estas frações. Todas as amostras mostraram atividade antioxidante, destacando-se a fração em AcOEt com melhor atividade e maior teor de fenólicos, então esta fração foi analisada por HPLC-DAD confirmando a presença de fenólicos. A atividade inibitória da topoisomerase II-α foi avaliada com as substâncias naturais litospermosida e γ- hidroxiferruginina A, isolado de Vismia guianensis e com o extrato EtOH bruto do látex desta espécie, e com as substâncias semi-sintéticas litospermosida peracetilada e dez flavonóides derivados de retusin, isolado de Solanum paludosum. Na concentração de 220 μM todas as amostras testadas apresentaram atividade, exceto a litospermosida e o seu derivado acetilado. Na concentração de 110 μM apenas dois flavonóides não inibiram a ação da topo II. A γ-hidroxiferruginina A inibiu a atividade da topo II em uma concentração mínima de 0,1 μM, sendo este antronóide prenilado um candidato promissor para estudos terapêuticos posteriores para o tratamento do câncer.

The species Bauhinia pentandra (Bong.) Vog. ex Steud (Leguminosae), known as mororó com espinho, is common in Northeast of Brazil. The enzyme DNA topoisomerase II-α (topo II) is responsible for the relaxation of the DNA during the processes of cellular division and is involved in diverse types of cancer, being considered a potential target in the treatment of the cancer. This work aimed to study the chemical composition and antioxidant activity of the bark roots of B. pentandra and the inhibition activity of topo II in natural and semi-synthetic compounds. In the chemical study of the vegetal species was isolated of the cyanogenic glycoside lithospermoside and a mixture of β-sitosterol and stigmasterol. The lithospermoside was acetylated and the structures had been identified through spectral data as IV and RMN1H and 13C including 2D. The Ethanolic extract and the fractions in…

Advisors/Committee Members: Creusioni Figueredo dos Santos, Tania Maria Sarmento da Silva.

Subjects/Keywords: Topoisomerase; FARMACOLOGIA; Litospermoside; Bauhinia; Topoisomerase; Litospermosida; Bauhinia

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APA (6^th Edition):

Lins, A. C. d. S. (2008). Estudo Químico e Atividade Antioxidante de Bauhinia Pentandra (Bong.) Vog. Ex Steud e Avaliação da Atividade Inibitória da Enzima Dna Topoisomerase II-a Humana de Substâncias Naturais e Semi-Sintéticas. (Thesis). Universidade Federal da Paraíba. Retrieved from http://bdtd.biblioteca.ufpb.br/tde_busca/arquivo.php?codArquivo=630 ; http://bdtd.biblioteca.ufpb.br/tde_busca/arquivo.php?codArquivo=631

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Lins, Antônio Claudio da Silva. “Estudo Químico e Atividade Antioxidante de Bauhinia Pentandra (Bong.) Vog. Ex Steud e Avaliação da Atividade Inibitória da Enzima Dna Topoisomerase II-a Humana de Substâncias Naturais e Semi-Sintéticas.” 2008. Thesis, Universidade Federal da Paraíba. Accessed April 12, 2021. http://bdtd.biblioteca.ufpb.br/tde_busca/arquivo.php?codArquivo=630 ; http://bdtd.biblioteca.ufpb.br/tde_busca/arquivo.php?codArquivo=631.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Lins, Antônio Claudio da Silva. “Estudo Químico e Atividade Antioxidante de Bauhinia Pentandra (Bong.) Vog. Ex Steud e Avaliação da Atividade Inibitória da Enzima Dna Topoisomerase II-a Humana de Substâncias Naturais e Semi-Sintéticas.” 2008. Web. 12 Apr 2021.

Vancouver:

Lins ACdS. Estudo Químico e Atividade Antioxidante de Bauhinia Pentandra (Bong.) Vog. Ex Steud e Avaliação da Atividade Inibitória da Enzima Dna Topoisomerase II-a Humana de Substâncias Naturais e Semi-Sintéticas. [Internet] [Thesis]. Universidade Federal da Paraíba; 2008. [cited 2021 Apr 12]. Available from: http://bdtd.biblioteca.ufpb.br/tde_busca/arquivo.php?codArquivo=630 ; http://bdtd.biblioteca.ufpb.br/tde_busca/arquivo.php?codArquivo=631.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Lins ACdS. Estudo Químico e Atividade Antioxidante de Bauhinia Pentandra (Bong.) Vog. Ex Steud e Avaliação da Atividade Inibitória da Enzima Dna Topoisomerase II-a Humana de Substâncias Naturais e Semi-Sintéticas. [Thesis]. Universidade Federal da Paraíba; 2008. Available from: http://bdtd.biblioteca.ufpb.br/tde_busca/arquivo.php?codArquivo=630 ; http://bdtd.biblioteca.ufpb.br/tde_busca/arquivo.php?codArquivo=631

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Rutgers University

2. Patel, Shivani, 1994-. Top2b deficiency affects retinal cell development.

Degree: MS, Biomedical Engineering, 2017, Rutgers University

URL: https://rucore.libraries.rutgers.edu/rutgers-lib/55609/

► Topoisomerase II beta (Top2b) is an enzyme that assists with DNA transcription by controlling the topological state of DNA to prevent supercoiling of the DNA… (more)

▼ Topoisomerase II beta (Top2b) is an enzyme that assists with DNA transcription by controlling the topological state of DNA to prevent supercoiling of the DNA and is widely expressed in postmitotic neurons. It is known to play a role in neuronal migration, cell adhesion, voltage-gated calcium channel activity, synaptic transmission, and cytoskeleton formation. In the retina, Top2b contributes to the late-stage differentiation and maturation of photoreceptors and affects the expression of key genes linked to retinopathies. Top2b deficiency has shown to lead to degeneration of the plexiform layers and outer segment of photoreceptors and reduction of cell number in the retina. However, the specific morphological differences between Top2b deficient retinal cells and normal retinal cells are not well documented. Additionally, the role of Top2b in interkinetic nuclear migration during retinal development has not been well defined. In this study, the role of Top2b in the developing retina was studied in two model systems: 1) the chick model was used to perform shRNA-based gene knockdown on cultured cells and retinal explants at embryonic day 10 (E10) to determine the function of Top2b at the embryonic stage; and 2) the gene knockout mouse model was used to examine tissue sections with Top2b deficiency at postnatal day 7 (P7), P14, and P21. In vitro shRNA knockdown was conducted to examine the role of Top2b in morphological development of the retina at the cellular level, while ex vivo and in vivo studies were used to examine cellular migration and morphology at the tissue level. Results show that i) after 3 days of Top2b knockdown in vitro, E10 retinal cells exhibit less surface area (3-fold reduction, p < 0.05) and shorter cellular processes (2-fold reduction, p < 0.05); ii) after 3 days of Top2b knockdown in the developing E10 chick retina, cells have shortened cellular processes but do not exhibit any migratory delays; iii) Top2b knockout delays interkinetic nuclear migration at P7 in the developing mouse retina, but does not inhibit migration of cells into the ONL in the long-term. This study helps to further characterize the role of Top2b in the developing retina and may provide insights into pathogenesis of various retinal disorders. Advisors/Committee Members: Cai, Li (chair), Sy, Jay (internal member), Schloss, Rene (internal member), School of Graduate Studies.

Subjects/Keywords: DNA topoisomerase II

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APA (6^th Edition):

Patel, Shivani, 1. (2017). Top2b deficiency affects retinal cell development. (Masters Thesis). Rutgers University. Retrieved from https://rucore.libraries.rutgers.edu/rutgers-lib/55609/

Chicago Manual of Style (16^th Edition):

Patel, Shivani, 1994-. “Top2b deficiency affects retinal cell development.” 2017. Masters Thesis, Rutgers University. Accessed April 12, 2021. https://rucore.libraries.rutgers.edu/rutgers-lib/55609/.

MLA Handbook (7^th Edition):

Patel, Shivani, 1994-. “Top2b deficiency affects retinal cell development.” 2017. Web. 12 Apr 2021.

Vancouver:

Patel, Shivani 1. Top2b deficiency affects retinal cell development. [Internet] [Masters thesis]. Rutgers University; 2017. [cited 2021 Apr 12]. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/55609/.

Council of Science Editors:

Patel, Shivani 1. Top2b deficiency affects retinal cell development. [Masters Thesis]. Rutgers University; 2017. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/55609/

Vanderbilt University

3. Ashley, Rachel Erin. Effects of DNA Geometry and Topoisomerase II Poisons on Human and Bacterial Type II Topoisomerases.

Degree: PhD, Biochemistry, 2017, Vanderbilt University

URL: http://hdl.handle.net/1803/10686

► The topological state of DNA has a dramatic effect on nucleic acid processes in cells. Type II topoisomerases are necessary enzymes that help regulate the… (more)

▼ The topological state of DNA has a dramatic effect on nucleic acid processes in cells. Type II topoisomerases are necessary enzymes that help regulate the topological state of the genome, but their activity requires the creation of transient DNA breaks. This potential to induce DNA damage is exploited by topoisomerase II poisons, which stabilize the covalent enzyme-cleaved DNA complex and eventually overwhelm the cell with DNA breaks. Although several topoisomerase II poisons are highly successful chemotherapeutic drugs or antibacterials, much about the interactions between topoisomerase II poisons, type II topoisomerases, and their DNA substrates has remained elusive. The first part of this dissertation examines interactions between human topoisomerase IIα and covalent poisons. Thymoquinone, a natural product from black seed, acts as a covalent poison even in its complex herbal form. This suggests that its chemopreventive properties may be related to its effects on topoisomerases. Covalent poisons cannot enhance cleavage mediated by the catalytic core of topoisomerase IIα, but can still inhibit the enzyme if incubated with it prior to the addition of DNA. Therefore, covalent poisons appear to have multiple interaction sites within the enzyme, although not every interaction stabilizes cleavage complexes. The second part of this dissertation describes the recognition of DNA geometry by bacterial type II topoisomerases. Bacillus anthracis gyrase relaxes overwound DNA quickly and processively while maintaining low levels of cleavage complexes, indicating that it is well suited to work on overwound DNA ahead of replication forks and tracking systems. Conversely, topoisomerase IV relaxes overwound DNA faster than underwound molecules but is unable to distinguish supercoil geometry during cleavage. Based on results with different constructs of Mycobacterium tuberculosis gyrase, it appears that the ability to distinguish supercoil geometry during cleavage is embedded within the N-terminal domain. Finally, the last part of this dissertation describes the biochemical basis of interactions between quinolone antibacterials and B. anthracis gyrase. Results indicate that the primary interaction occurs through a conserved water-metal ion bridge. However, altering quinolone substituents can allow for new interactions and overcome resistance. Advisors/Committee Members: Neil Osheroff, Ph.D. (committee member), Charles R. Sanders, Ph.D. (committee member), Eric P. Skaar, Ph.D., M.P.H. (committee member), Timothy R. Sterling, M.D. (committee member), John D. York, Ph.D. (Committee Chair).

Subjects/Keywords: DNA topology; topoisomerase II poisons; quinolone; gyrase; topoisomerase IV; topoisomerase IIalpha

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ashley, R. E. (2017). Effects of DNA Geometry and Topoisomerase II Poisons on Human and Bacterial Type II Topoisomerases. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10686

Chicago Manual of Style (16^th Edition):

Ashley, Rachel Erin. “Effects of DNA Geometry and Topoisomerase II Poisons on Human and Bacterial Type II Topoisomerases.” 2017. Doctoral Dissertation, Vanderbilt University. Accessed April 12, 2021. http://hdl.handle.net/1803/10686.

MLA Handbook (7^th Edition):

Ashley, Rachel Erin. “Effects of DNA Geometry and Topoisomerase II Poisons on Human and Bacterial Type II Topoisomerases.” 2017. Web. 12 Apr 2021.

Vancouver:

Ashley RE. Effects of DNA Geometry and Topoisomerase II Poisons on Human and Bacterial Type II Topoisomerases. [Internet] [Doctoral dissertation]. Vanderbilt University; 2017. [cited 2021 Apr 12]. Available from: http://hdl.handle.net/1803/10686.

Council of Science Editors:

Ashley RE. Effects of DNA Geometry and Topoisomerase II Poisons on Human and Bacterial Type II Topoisomerases. [Doctoral Dissertation]. Vanderbilt University; 2017. Available from: http://hdl.handle.net/1803/10686

University of Edinburgh

4. Corless, Samuel. Role of DNA supercoiling in genome structure and regulation.

Degree: PhD, 2014, University of Edinburgh

URL: http://hdl.handle.net/1842/9623

► A principle challenge of modern biology is to understand how the human genome is organised and regulated within a nucleus. The field of chromatin biology… (more)

▼ A principle challenge of modern biology is to understand how the human genome is organised and regulated within a nucleus. The field of chromatin biology has made significant progress in characterising how protein and DNA modifications reflect transcription and replication state. Recently our lab has shown that the human genome is organised into large domains of altered DNA helical twist, called DNA supercoiling domains, similar to the regulatory domains observed in prokaryotes. In my PhD I have analysed how the maintenance and distribution of DNA supercoiling relates to biological function in human cells. DNA supercoiling domains are set up and maintained by the balanced activity of RNA transcription and topoisomerase enzymes. RNA polymerase twists the DNA, over-winding in front of the polymerase and under-winding behind. In contrast topoisomerases relieve supercoiling from the genome by introducing transient nicks (topoisomerase I) or double strand breaks (topoisomerase II) into the double helix. Topoisomerase activity is critical for cell viability, but the distribution of topoisomerase I, IIα and IIβ in the human genome is not known. Using a chromatin immunoprecipitation (ChIP) approach I have shown that topoisomerases are enriched in large chromosomal domains, with distinct topoisomerase I and topoisomerase II domains. Topoisomerase I is correlated with RNA polymerase II, genes and underwound DNA, whereas topoisomerase IIα and IIβ are associated with each other and over-wound DNA. This indicates that different topoisomerase proteins operate in distinct regions of the genome and can be independently regulated depending on the genomic environment. Transcriptional regulation by DNA supercoiling is believed to occur through changes in gene promoter structure. To investigate DNA supercoiling my lab has developed biotinylated trimethylpsoralen (bTMP) as a DNA structure probe, which preferentially intercalates into under-wound DNA. Using bTMP in conjunction with microarrays my lab identified a transcription and topoisomerase dependent peak of under-wound DNA in a meta-analysis of several hundred genes (Naughton et al. (2013)). In a similar analysis, Kouzine et al. (2013) identified an under-wound promoter structure and proposed a model of topoisomerase distribution for the regulation of promoter DNA supercoiling. To better understand the role of supercoiling and topoisomerases at gene promoters, a much larger-scale analysis of these factors was required. I have analysed the distribution of bTMP at promoters genome wide, confirming a transcription and expression dependent distribution of DNA supercoils. DNA supercoiling is distinct at CpG island and non-CpG island promoters, and I present a model in which over-wound DNA limits transcription from both CpG island promoters and repressed genes. In addition, I have mapped by ChIP topoisomerase I and IIβ at gene promoters on chromosome 11 and identified a different distribution to that proposed by Kouzine et al. (2013), with topoisomerase I maintaining DNA supercoiling at…

Subjects/Keywords: 572; DNA supercoiling; RNA transcription; topoisomerase enzymes; topoisomerase I; topoisomerase II; CpG island

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Corless, S. (2014). Role of DNA supercoiling in genome structure and regulation. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/9623

Chicago Manual of Style (16^th Edition):

Corless, Samuel. “Role of DNA supercoiling in genome structure and regulation.” 2014. Doctoral Dissertation, University of Edinburgh. Accessed April 12, 2021. http://hdl.handle.net/1842/9623.

MLA Handbook (7^th Edition):

Corless, Samuel. “Role of DNA supercoiling in genome structure and regulation.” 2014. Web. 12 Apr 2021.

Vancouver:

Corless S. Role of DNA supercoiling in genome structure and regulation. [Internet] [Doctoral dissertation]. University of Edinburgh; 2014. [cited 2021 Apr 12]. Available from: http://hdl.handle.net/1842/9623.

Council of Science Editors:

Corless S. Role of DNA supercoiling in genome structure and regulation. [Doctoral Dissertation]. University of Edinburgh; 2014. Available from: http://hdl.handle.net/1842/9623

Vanderbilt University

5. Gentry, Amanda Cormine. Role of DNA interactions in modulating the activity of human topoisomerases and anticancer drugs.

Degree: PhD, Biochemistry, 2011, Vanderbilt University

URL: http://hdl.handle.net/1803/10781

► Human topoisomerase I and topoisomerase IIα and IIβ play critical roles in regulating the topological state of DNA and are targets for some of the… (more)

▼ Human topoisomerase I and topoisomerase IIα and IIβ play critical roles in regulating the topological state of DNA and are targets for some of the most widely prescribed anticancer drugs currently in clinical use. These drugs act by stabilizing covalent-topoisomerase cleavage complexes that are requisite intermediates in the enzyme catalytic cycles. It is the accumulation of these cleavage complexes ahead of DNA tracking systems, on overwound DNA, that ultimately leads to cell death. Therefore, work in this dissertation more fully characterizes the effects that DNA interactions have on the activities of topoisomerase I and topoisomerase II and drugs that target these enzymes. Results show that all clusters of positively charged residues located in the C-terminal domain of topoisomerases IIα are necessary for the preferential relaxation of overwound substrates. Experiments also show that topoisomerase I preferentially relaxes and cleaves overwound substrates in the absence or presence of anticancer drugs. Additionally, DNA intercalating compounds were found to act as ‘topological poisons’ of topoisomerase I, enhancing cleavage activity on underwound substrates and in cells by changing the apparent topological state of the DNA. Finally, F14512, an etoposide derivative that contains a spermine moiety in place of the C4 carbohydrate, was shown to be a more potent poison of human topoisomerase II than the parent compound. The drug shows similar contacts as etoposide in the enzyme-drug binary complex but, unlike etoposide, interacts with DNA in the absence of enzyme. The enhanced activity of the drug correlates with a stronger interaction of the compound in the ternary enzyme-drug-DNA complex, and the covalent linkage of the spermine moiety to the drug core is necessary for this enhanced activity. Together, data presented in this dissertation increase our understanding of the role that topoisomerase-DNA interactions play in enzyme regulation of DNA topology and highlight the importance of enzyme-DNA-drug interactions when designing new topoisomerase-targeted compounds with potentially enhanced therapeutic potential. Advisors/Committee Members: Dr. Daniel Kaplan (committee member), Dr. Martin Egli (committee member), Dr. Zu-Wen Sun (committee member), Dr. Michael Stone (committee member), Dr. Neil Osheroff (Committee Chair).

Subjects/Keywords: DNA; topology; anticancer drugs; topoisomerase

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gentry, A. C. (2011). Role of DNA interactions in modulating the activity of human topoisomerases and anticancer drugs. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10781

Chicago Manual of Style (16^th Edition):

Gentry, Amanda Cormine. “Role of DNA interactions in modulating the activity of human topoisomerases and anticancer drugs.” 2011. Doctoral Dissertation, Vanderbilt University. Accessed April 12, 2021. http://hdl.handle.net/1803/10781.

MLA Handbook (7^th Edition):

Gentry, Amanda Cormine. “Role of DNA interactions in modulating the activity of human topoisomerases and anticancer drugs.” 2011. Web. 12 Apr 2021.

Vancouver:

Gentry AC. Role of DNA interactions in modulating the activity of human topoisomerases and anticancer drugs. [Internet] [Doctoral dissertation]. Vanderbilt University; 2011. [cited 2021 Apr 12]. Available from: http://hdl.handle.net/1803/10781.

Council of Science Editors:

Gentry AC. Role of DNA interactions in modulating the activity of human topoisomerases and anticancer drugs. [Doctoral Dissertation]. Vanderbilt University; 2011. Available from: http://hdl.handle.net/1803/10781

Boston University

6. Godley IV, Frederick Augustus. Examining the association between BRCA1 and topoisomerase I in cancer cells in response to camptothecin treatment.

Degree: MS, Medical Sciences, 2015, Boston University

URL: http://hdl.handle.net/2144/16005

► DNA topoisomerase I (TopoI) is an essential enzyme involved in the relief of DNA supercoiling during replication. TopoI plays important role in various DNA events,… (more)

Subjects/Keywords: Oncology; BRCA1; Camptothecins; Topoisomerase I

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Godley IV, F. A. (2015). Examining the association between BRCA1 and topoisomerase I in cancer cells in response to camptothecin treatment. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/16005

Chicago Manual of Style (16^th Edition):

Godley IV, Frederick Augustus. “Examining the association between BRCA1 and topoisomerase I in cancer cells in response to camptothecin treatment.” 2015. Masters Thesis, Boston University. Accessed April 12, 2021. http://hdl.handle.net/2144/16005.

MLA Handbook (7^th Edition):

Godley IV, Frederick Augustus. “Examining the association between BRCA1 and topoisomerase I in cancer cells in response to camptothecin treatment.” 2015. Web. 12 Apr 2021.

Vancouver:

Godley IV FA. Examining the association between BRCA1 and topoisomerase I in cancer cells in response to camptothecin treatment. [Internet] [Masters thesis]. Boston University; 2015. [cited 2021 Apr 12]. Available from: http://hdl.handle.net/2144/16005.

Council of Science Editors:

Godley IV FA. Examining the association between BRCA1 and topoisomerase I in cancer cells in response to camptothecin treatment. [Masters Thesis]. Boston University; 2015. Available from: http://hdl.handle.net/2144/16005

University of New South Wales

7. Trivedi, Shuchi. Topoisomerase I is required for the expression of long genes in glial cells and is dysregulated in ASD brain.

Degree: Biotechnology & Biomolecular Sciences, 2018, University of New South Wales

URL: http://handle.unsw.edu.au/1959.4/62211 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:58255/SOURCE02?view=true

► Autism spectrum disorder (ASD) is a neurodevelopmental disease which is a highly heritable, but genetically heterogeneous. With increasing prevalence in last decade, it affects 1-2%… (more)

▼ Autism spectrum disorder (ASD) is a neurodevelopmental disease which is a highly heritable, but genetically heterogeneous. With increasing prevalence in last decade, it affects 1-2% population of the world, with the occurrence ratio of female to male being 1:4. Accumulating evidence suggests that ASD may be caused by synaptic dysfunction. At the same time, genes involved in synaptic function are often long genes (>100kb). Perturbation of long gene expression, and consequently synaptic homeostasis has been hypothesized to be involved in neurodevelopmental diseases. How the expression of long genes in the brain is regulated, and potentially altered in neurodevelopmental disorders remains unclear. Recent studies have shown that Topoisomerase 1 (TOP1), a ubiquitously expressed enzyme involved in DNA replication and repair, is required for the expression of long genes in neurons. However, whether this effect is cell-type specific in the brain has not been elucidated. Furthermore, genetic variants in topoisomerase genes have been identified in ASD individuals, raising a potential link between the dysregulation of long genes and TOP1 in ASD. The current study was carried out to (a) assess the cell-type specificity of TOP1’s effect on long gene transcription in the brain and (b) investigate the expression of TOP1 and TOP1-dependent genes in brain tissue from ASD and control individuals. By assessing the effect of TOP1 inhibition on long gene expression in glial cells (i.e. normal human astrocytes), the current study extended the role of TOP1 in regulating long gene expression to all major brain cell types and determined that the expression of long genes was inversely proportional to their length. We also demonstrate for the first time that TOP1 expression is enriched in the cerebellum compared to human cerebral cortex and that it is overexpressed in ASD brain samples. Furthermore, some of the TOP1-dependent genes also show increases in gene expression in ASD brain. Advisors/Committee Members: Voineagu, Irina, Biotechnology & Biomolecular Sciences, Faculty of Science, UNSW.

Subjects/Keywords: ASD; Topoisomerase; Long genes; Astrocytes

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Trivedi, S. (2018). Topoisomerase I is required for the expression of long genes in glial cells and is dysregulated in ASD brain. (Masters Thesis). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/62211 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:58255/SOURCE02?view=true

Chicago Manual of Style (16^th Edition):

Trivedi, Shuchi. “Topoisomerase I is required for the expression of long genes in glial cells and is dysregulated in ASD brain.” 2018. Masters Thesis, University of New South Wales. Accessed April 12, 2021. http://handle.unsw.edu.au/1959.4/62211 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:58255/SOURCE02?view=true.

MLA Handbook (7^th Edition):

Trivedi, Shuchi. “Topoisomerase I is required for the expression of long genes in glial cells and is dysregulated in ASD brain.” 2018. Web. 12 Apr 2021.

Vancouver:

Trivedi S. Topoisomerase I is required for the expression of long genes in glial cells and is dysregulated in ASD brain. [Internet] [Masters thesis]. University of New South Wales; 2018. [cited 2021 Apr 12]. Available from: http://handle.unsw.edu.au/1959.4/62211 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:58255/SOURCE02?view=true.

Council of Science Editors:

Trivedi S. Topoisomerase I is required for the expression of long genes in glial cells and is dysregulated in ASD brain. [Masters Thesis]. University of New South Wales; 2018. Available from: http://handle.unsw.edu.au/1959.4/62211 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:58255/SOURCE02?view=true

Purdue University

8. Beck, Daniel Edward. DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS.

Degree: PhD, Medicinal Chemistry and Molecular Pharmacology, 2015, Purdue University

URL: https://docs.lib.purdue.edu/open_access_dissertations/1166

► The research in this thesis is focused on the design, synthesis, and biological evaluation of indenoisoquinolines that inhibit the human topoisomerase IB enzyme (Top1). At… (more)

Subjects/Keywords: indenoisoquinoline; medicinal; synthesis; topoisomerase I

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Beck, D. E. (2015). DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS. (Doctoral Dissertation). Purdue University. Retrieved from https://docs.lib.purdue.edu/open_access_dissertations/1166

Chicago Manual of Style (16^th Edition):

Beck, Daniel Edward. “DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS.” 2015. Doctoral Dissertation, Purdue University. Accessed April 12, 2021. https://docs.lib.purdue.edu/open_access_dissertations/1166.

MLA Handbook (7^th Edition):

Beck, Daniel Edward. “DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS.” 2015. Web. 12 Apr 2021.

Vancouver:

Beck DE. DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS. [Internet] [Doctoral dissertation]. Purdue University; 2015. [cited 2021 Apr 12]. Available from: https://docs.lib.purdue.edu/open_access_dissertations/1166.

Council of Science Editors:

Beck DE. DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS. [Doctoral Dissertation]. Purdue University; 2015. Available from: https://docs.lib.purdue.edu/open_access_dissertations/1166

9. PEDROSA, Sybelle Christianne Batista de Lacerda. Síntese, caracterização estrutural e estudos do mecanismo de ação antitumoral de derivados indólicos.

Degree: 2017, Federal University of Pernambuco

URL: https://repositorio.ufpe.br/handle/123456789/25346

► O câncer é caracterizado por crescimento celular descontrolado e capacidade de migração celular do local de origem para outros órgãos, o que pode resultar em… (more)

▼ O câncer é caracterizado por crescimento celular descontrolado e capacidade de migração celular do local de origem para outros órgãos, o que pode resultar em morte. Apesar dos avanços na compreensão dos mecanismos envolvidos nesta patologia e os progressos realizados na terapêutica do câncer, a toxicidade e a resistência aos fármacos tradicionais ainda constituem um grande desafio no tratamento do câncer. Assim, torna-se relevante o desenvolvimento de novos fármacos e pesquisas por novos alvos terapêuticos buscando obter êxito na terapia do câncer. Nesta perspectiva, este trabalho propôs a síntese de dezesseis compostos indólicos-tiossemicarbazonas e a partir destes foram realizadas reações de ciclização obtendo-se dez derivados 4-tiazolidinonas. Além disso, foi verificada a atividade antiproliferativa in vitro, analisada a capacidade de interação com o DNA, avaliada a atividade inibitória topoisomerase IIα e verificada a capacidade de induzir a morte celular na linhagem tumoral mais sensível do ensaio antiproliferativo. As moléculas foram obtidas através de rotas sintéticas eficazes, rendimentos satisfatórios e ponto de fusão na faixa de pureza. Todas as estruturas foram caracterizadas e comprovadas por espectrometria de massas (MS), infravermelho (IV), metódos espectroscópicos unidimensionais de RMN ¹H e RMN ¹³C, e técnicas espectroscópicas bidimensionais, como COSY ¹H-¹H, HSQC ¹H-¹³C e NOESY. Os compostos indólicos-tiossemicarbazonas foram testados quanto à atividade antitumoral in vitro, por meio de ensaio antiproliferativo Sulforrodamina B frente às linhagens de células tumorais de mama (MCF-7), ovário (OVCAR-03), ovário resistente a múltiplas drogas (NCI-ADR/RES), pulmão (NCI-H460), cólon (HT-29), rim (786-0), leucemia (K-562) e glioma (U-251). Neste teste, o composto LqIT/LT-51 mostrou-se o mais ativo da série, destacando se frente às linhagens HT-29 e K-562 com valores de GI₅₀ (concentração molar do composto que inibe 50% do crescimento celular) = 0.01 μM, para ambas as linhagens. Com isso, o derivado LqIT/LT-51 foi conduzido para análise da interação com o DNA por meio da espectroscopia de absorção e emissão da fluorescência. O LqIT/LT-51 mostrou alterações em suas propriedades espectroscópicas após a ligação com DNA, apresentando efeito hipercrômico e sugerindo mudanças na conformação da estrutura do DNA. A constante de ligação (Kb) calculada foi 4.30 x 10⁴. A supressão da fluorescência (Ksv) apresentou o valor de 1.19 x 10³ M¹, indicando afinidade pelos pares de base do DNA. A atividade de LqIT/LT-51 como inibidor topoisomerase IIα foi visualizada nas concentrações de 50 e 100 μM, e ambas as concentrações produziram inibição enzimática parcial. Na análise da indução da morte celular, o LqIT/LT-51 induziu a morte celular, possivelmente apoptótica nas células de HT-29 de forma concentração-dependente e promoveu a parada do ciclo na fase G2/M. Estes resultados mostraram que o núcleo indol, a tiossemicarbazona e o grupo 1-naftil são promissores scaffolds para o desenvolvimento de novos fármacos com potencial… Advisors/Committee Members: http://lattes.cnpq.br/7568400311889864, LIMA, Maria do Carmo Alves de, OLIVEIRA, Jamerson Ferreira de.

Subjects/Keywords: Indol; DNA; Topoisomerase; Câncer

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

PEDROSA, S. C. B. d. L. (2017). Síntese, caracterização estrutural e estudos do mecanismo de ação antitumoral de derivados indólicos. (Doctoral Dissertation). Federal University of Pernambuco. Retrieved from https://repositorio.ufpe.br/handle/123456789/25346

Chicago Manual of Style (16^th Edition):

PEDROSA, Sybelle Christianne Batista de Lacerda. “Síntese, caracterização estrutural e estudos do mecanismo de ação antitumoral de derivados indólicos.” 2017. Doctoral Dissertation, Federal University of Pernambuco. Accessed April 12, 2021. https://repositorio.ufpe.br/handle/123456789/25346.

MLA Handbook (7^th Edition):

PEDROSA, Sybelle Christianne Batista de Lacerda. “Síntese, caracterização estrutural e estudos do mecanismo de ação antitumoral de derivados indólicos.” 2017. Web. 12 Apr 2021.

Vancouver:

PEDROSA SCBdL. Síntese, caracterização estrutural e estudos do mecanismo de ação antitumoral de derivados indólicos. [Internet] [Doctoral dissertation]. Federal University of Pernambuco; 2017. [cited 2021 Apr 12]. Available from: https://repositorio.ufpe.br/handle/123456789/25346.

Council of Science Editors:

PEDROSA SCBdL. Síntese, caracterização estrutural e estudos do mecanismo de ação antitumoral de derivados indólicos. [Doctoral Dissertation]. Federal University of Pernambuco; 2017. Available from: https://repositorio.ufpe.br/handle/123456789/25346

10. PONTES, Catharine de Araújo Crisóstomo. Perfil imunocitoquímico das proteínas Ki-67 e TOPIIα em pacientes com anormalidades cervicais.

Degree: 2017, Federal University of Pernambuco

URL: https://repositorio.ufpe.br/handle/123456789/25019

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O câncer cervical é a quarta neoplasia mais diagnosticada em mulheres no mundo e tem como principal agente etiológico a infecção pelo Papillomavirus Humano (HPV),… (more)

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O câncer cervical é a quarta neoplasia mais diagnosticada em mulheres no mundo e tem como principal agente etiológico a infecção pelo Papillomavirus Humano (HPV), que induz à proliferação descontrolada das células, levando ao acúmulo de mutações ao longo do tempo podendo levar ao câncer. A expressão anormal de proteínas nucleares, como Ki-67 e TOPIIα, indica desregulação do ciclo celular e pode, em conjunto com outros testes, melhorar a acurácia dos programas de rastreamento. Este estudo objetivou avaliar a detecção dos marcadores Ki-67 e TOPIIα, através da técnica de imunocitoquímica, em pacientes com anormalidades cervicais, observando a possibilidade de detectar lesões clinicamente relevantes, melhorando a sensibilidade da citologia. Participaram do estudo 76 mulheres encaminhadas a um Centro de referência por apresentarem alterações em exames anteriores ou mesmo condilomas, que representam a infecção clínica pelo HPV. Observou-se um maior índice de positividade (IP) de Ki-67 e TOPIIα nas pacientes diagnosticadas com anormalidades cervicais detectadas pela citologia (41,6% e 62,5%, respectivamente). O desempenho do Ki-67 foi melhor em pacientes com LSIL (IP igual a 50%), e TOPIIα teve um melhor desempenho em pacientes com HSIL (66,6%). O teste de associação entre a imunocitoquímica e a citologia em base líquida revelou-se estatisticamente significante (p< 0,05) com valor de p=0,0026 para Ki-67 e p=0,0004 para TOPIIα. Os marcadores analisados, Ki-67 e TOPIIα, se mostraram eficientes na detecção de lesões cervicais clinicamente relevantes, dada a forte associação entre a expressão desses marcadores em pacientes diagnosticadas com anormalidades cervicais pela citologia.

Cervical cancer is the fourth most diagnosed neoplasia in women in the world and its main etiological agent is infection by the Human Papillomavirus (HPV), which induces the uncontrolled proliferation of cells, leading to the accumulation of mutations over time and to cancer in some cases. The abnormal expression of nuclear proteins, such as Ki-67 and TOPIIα, indicating dysregulation of the cell cycle and can, in conjunction with other tests, improve the accuracy of screening programs. This study aimed to evaluate the detection of Ki-67 and TOPIIα, through the technique of immunocytochemistry in patients with cervical abnormalities, noting whether they are useful to detect clinically relevant lesions, improving the sensitivity of cytology. 76 women participated in the study referred to a reference centre for presenting changes in previous tests or even Condyloma, representing clinical infection by HPV. It was observed a higher rate of positivity (IP) of Ki-67 and TOPIIα in patients diagnosed with cervical abnormalities detected by cytology (41.6% and 62.5%, respectively). Seventh six women participated in the study referred to a reference centre for presenting changes in previous tests or even condylomas, representing clinical infection by HPV. It was observed a higher rate of positivity (RP) of Ki-67 and TOPIIα in patients diagnosed with cervical…

Advisors/Committee Members: http://lattes.cnpq.br/6226838543372982, MELO JÚNIOR, Mario Ribeiro de, MEDEIROS, Adrya Lúcia Peres Bezerra de.

Subjects/Keywords: Topoisomerase; Cervicite uterina; Imunocitoquímica; HPV

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

PONTES, C. d. A. C. (2017). Perfil imunocitoquímico das proteínas Ki-67 e TOPIIα em pacientes com anormalidades cervicais. (Masters Thesis). Federal University of Pernambuco. Retrieved from https://repositorio.ufpe.br/handle/123456789/25019

Chicago Manual of Style (16^th Edition):

PONTES, Catharine de Araújo Crisóstomo. “Perfil imunocitoquímico das proteínas Ki-67 e TOPIIα em pacientes com anormalidades cervicais.” 2017. Masters Thesis, Federal University of Pernambuco. Accessed April 12, 2021. https://repositorio.ufpe.br/handle/123456789/25019.

MLA Handbook (7^th Edition):

PONTES, Catharine de Araújo Crisóstomo. “Perfil imunocitoquímico das proteínas Ki-67 e TOPIIα em pacientes com anormalidades cervicais.” 2017. Web. 12 Apr 2021.

Vancouver:

PONTES CdAC. Perfil imunocitoquímico das proteínas Ki-67 e TOPIIα em pacientes com anormalidades cervicais. [Internet] [Masters thesis]. Federal University of Pernambuco; 2017. [cited 2021 Apr 12]. Available from: https://repositorio.ufpe.br/handle/123456789/25019.

Council of Science Editors:

PONTES CdAC. Perfil imunocitoquímico das proteínas Ki-67 e TOPIIα em pacientes com anormalidades cervicais. [Masters Thesis]. Federal University of Pernambuco; 2017. Available from: https://repositorio.ufpe.br/handle/123456789/25019

11. Xavier, Patricia Mendes Jorge. Indução de parada no ciclo celular e apoptose pelo ditelureto de difenila : uma possível relação com inibição de enzimas topoisomerases.

Degree: 2012, Brazil

URL: http://hdl.handle.net/10183/84960

►

O ditelureto difenila (DTDF) é um protótipo para o desenvolvimento de novas moléculas biologicamente ativas. Estudos prévios caracterizaram o efeito citotóxico dessa molécula em fibroblastos… (more)

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O ditelureto difenila (DTDF) é um protótipo para o desenvolvimento de novas moléculas biologicamente ativas. Estudos prévios caracterizaram o efeito citotóxico dessa molécula em fibroblastos de pulmão de hamster chinês (células V79) mas os mecanismos relacionados à redução da viabilidade pelo DTDF são pouco conhecidos. Portanto, neste trabalho foi investigado o tipo de morte celular provocada pelo DTDF, sua influência no ciclo celular e sua possível interação com enzimas topoisomerases empregando células V79 e a levedura Saccharomyces cerevisiae como modelos biológicos de estudo. Conforme esperado, houve redução da viabilidade celular após o tratamento DTDF observada pelo ensaio MTT. A análise morfológica por coloração diferencial mostrou ocorrência de células apoptóticas e necróticas. Um aumento da atividade da enzima caspase 3/7 confirma a indução de apoptose pelo DTDF. Foi observada parada na progressão do ciclo celular na fase S e em sub-G1. A interação com topoisomerases foi verificada pelo teste de micronúcleo (MN) em células V79 onde foi verificado um possível potencial intercalante do DPDT. Linhagens de levedura deficientes em Top1p apresentaram maior tolerância ao DTDF em relação à linhagem selvagem, sugerindo que a interação com a enzima pode estar envolvida na toxicidade do DTDF. A sensibilidade ao DTDF encontrada na linhagem top3Δ indica que Top3p pode participar na reparação das lesões do DNA induzidas por este composto. Os nossos resultados sugerem que a diminuição da viabilidade celular pode ser atribuída à interação do DTDF com enzimas topoisomerases, levando a formação de quebras no DNA com consequente parada no ciclo celular e morte celular por apoptose/necrose.

The diphenyl ditelluride (DPDT) is a prototype for the development of new biologically active molecules. In previous studies, this organotelluride has shown an elevated cytotoxicity in lung fibroblast cell line derived from Chinese hamster (V79 cells), but the mechanisms for reduction of cell viability still remain unknown. Therefore, in this study we investigate the type of cell death induced by DPDT, the influence on cell cycle and its possible interaction with topoisomerase enzymes using V79 cells and the Saccharomyces cerevisiae yeast as biological models of study. As expected, there was a reduction in cell viability after DPDT treatment observed by MTT assay. Morphological analysis showed significant elevation in apoptotic and necrotic cells. An increase of caspase 3/7 activity confirms the apoptosis induction by DPDT. The arrest in the progression of the cell cycle in S phase and in sub-G1 was observed. The interaction with DNA topoisomerases was verified by the micronucleus test (MN) in V79 cells, which showed a possible intercalating potential of DPDT. Yeast strain deficient in Top1p showed higher tolerance to DPDT in relation to the wild type isogenic strain, suggesting that the interaction with this enzyme could be involved in the toxicity of DPDT. The sensitivity to DPDT found in top3Δ strain indicates that Top3p could…

Advisors/Committee Members: Henriques, João Antonio Pêgas.

Subjects/Keywords: Telúrio; Apoptose; DNA topoisomerase

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Xavier, P. M. J. (2012). Indução de parada no ciclo celular e apoptose pelo ditelureto de difenila : uma possível relação com inibição de enzimas topoisomerases. (Masters Thesis). Brazil. Retrieved from http://hdl.handle.net/10183/84960

Chicago Manual of Style (16^th Edition):

Xavier, Patricia Mendes Jorge. “Indução de parada no ciclo celular e apoptose pelo ditelureto de difenila : uma possível relação com inibição de enzimas topoisomerases.” 2012. Masters Thesis, Brazil. Accessed April 12, 2021. http://hdl.handle.net/10183/84960.

MLA Handbook (7^th Edition):

Xavier, Patricia Mendes Jorge. “Indução de parada no ciclo celular e apoptose pelo ditelureto de difenila : uma possível relação com inibição de enzimas topoisomerases.” 2012. Web. 12 Apr 2021.

Vancouver:

Xavier PMJ. Indução de parada no ciclo celular e apoptose pelo ditelureto de difenila : uma possível relação com inibição de enzimas topoisomerases. [Internet] [Masters thesis]. Brazil; 2012. [cited 2021 Apr 12]. Available from: http://hdl.handle.net/10183/84960.

Council of Science Editors:

Xavier PMJ. Indução de parada no ciclo celular e apoptose pelo ditelureto de difenila : uma possível relação com inibição de enzimas topoisomerases. [Masters Thesis]. Brazil; 2012. Available from: http://hdl.handle.net/10183/84960

Technical University of Lisbon

12. Pereira, Octávio José Carraça. Fluoroquinolonas como inibidoras das topoisomerases de Leishmania infantum.

Degree: 2015, Technical University of Lisbon

URL: http://www.rcaap.pt/detail.jsp?id=oai:www.repository.utl.pt:10400.5/9090

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Dissertação de Mestrado Integrado em Medicina Veterinária

A leishmaniose é uma das principais doenças negligenciadas, com uma incidência de 1,3 milhões de casos anuais em… (more)

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Dissertação de Mestrado Integrado em Medicina Veterinária

A leishmaniose é uma das principais doenças negligenciadas, com uma incidência de 1,3 milhões de casos anuais em humanos, dos quais se estima que resultem 20 mil a 30 mil fatalidades. O objectivo deste estudo foi avaliar a eficácia de 12 fluoroquinolonas, 2 isoflavonas e 1 aminocumarina na inibição do crescimento e efeito citotóxico de promastigotas de Leishmania infantum cultivados axenicamente. Os parasitas foram obtidos de animais diagnosticados com leishmaniose e cultivados em meio RPMI-1640 enriquecido com hemina, aminoácidos essenciais e urina humana, de acordo com uma adaptação dos métodos descritos na bibliografia, e incubados num dispositivo de baixo custo, construído para o efeito. As subculturas em fase logarímica foram tratadas durante 7 dias com 5 concentrações dos compostos. O grupo de controlo foi tratado com 3 concentrações de antimoniato de n-metilglucamina. Os efeitos foram medidos através da alteração da absorvência do meio de cultura após reacção de conversão de MTS, e por observação (microscopia óptica) de alterações morfométricas dos promastigotas. Nos testes a Balofloxacina, a Gemifloxacina e a Clinafloxacina mostraram os efeitos mais marcantes e LC50 menores. Os resultados sugerem o interesse no desenvolvimento de futuros testes in vitro e in vivo.

ABSTRACT - Leishmaniasis is one of the major neglected diseases, with an incidence of 1,3 million human cases annualy, of which an estimated 20.000 to 30.000 outcome in death. The aim of this study was to investigate the efficacy of 12 fluoroquinolones, 2 isoflavones and 1 aminocumarine in inhibiting the growth and possible cytotoxic effect on axenically grown Leishmania infantum promastigotes. The parasites were obtained from animals diagnosed with leishmaniasis and maintained in RPMI-1640 medium, supplemented with hemin, essential amino acids and human urine, in an adaptadion of methods previously described, and incubated in a purpose-built low cost device. Subcultures in log-phase were treated for 7 days with 5 fluoroquinolones concentrations. The control group was treated with 3 concentrations of meglumine antimoniate.. The effects were measured using the change in absorbance of the culture medium after MTS conversion reaction, and by optical microscopy observation of the morphometric changes in the promastigote population. In tests, Balofloxacine, Gemifloxacine and Clinafloxacine showed the most marked effects and lower LC50. The results suggest the interest in developing future tests in vitro and in vivo.

Advisors/Committee Members: Sampaio, Isabel Maria Soares Pereira da Fonseca de, Ferreira, Fernando António da Costa.

Subjects/Keywords: Leishmaniose; Leishmania infantum; Fluoroquinolona; Topoisomerase; Leishmaniosis; Leishmania infantum; Fluoroquinolone; Topoisomerase

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pereira, O. J. C. (2015). Fluoroquinolonas como inibidoras das topoisomerases de Leishmania infantum. (Thesis). Technical University of Lisbon. Retrieved from http://www.rcaap.pt/detail.jsp?id=oai:www.repository.utl.pt:10400.5/9090

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Pereira, Octávio José Carraça. “Fluoroquinolonas como inibidoras das topoisomerases de Leishmania infantum.” 2015. Thesis, Technical University of Lisbon. Accessed April 12, 2021. http://www.rcaap.pt/detail.jsp?id=oai:www.repository.utl.pt:10400.5/9090.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Pereira, Octávio José Carraça. “Fluoroquinolonas como inibidoras das topoisomerases de Leishmania infantum.” 2015. Web. 12 Apr 2021.

Vancouver:

Pereira OJC. Fluoroquinolonas como inibidoras das topoisomerases de Leishmania infantum. [Internet] [Thesis]. Technical University of Lisbon; 2015. [cited 2021 Apr 12]. Available from: http://www.rcaap.pt/detail.jsp?id=oai:www.repository.utl.pt:10400.5/9090.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Pereira OJC. Fluoroquinolonas como inibidoras das topoisomerases de Leishmania infantum. [Thesis]. Technical University of Lisbon; 2015. Available from: http://www.rcaap.pt/detail.jsp?id=oai:www.repository.utl.pt:10400.5/9090

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Johannes Gutenberg Universität Mainz

13. Frensch, Isabelle. Die Rolle der Topoisomerase 2 beta in der normalen Herzfunktion sowie in der Entstehung der Herzinsuffizienz.

Degree: 2014, Johannes Gutenberg Universität Mainz

URL: http://ubm.opus.hbz-nrw.de/volltexte/2014/3900/

► Die Herzinsuffizienz (HI) ist eine der häufigsten und teuersten medizinischen Indikationen in der heutigen Zeit. rnIn der vorliegenden Arbeit konnte zum ersten Mal die Topoisomerase… (more)

▼ Die Herzinsuffizienz (HI) ist eine der häufigsten und teuersten medizinischen Indikationen in der heutigen Zeit. rnIn der vorliegenden Arbeit konnte zum ersten Mal die Topoisomerase 2b (Top2b) in Zusammenhang mit der Entstehung einer dilatativen Kardiomyopathie gebracht werden. rnIn einem speziellen Mausmodell war es möglich, die Top2b gewebsspezifisch und zeitspezifisch nur in Kardiomyozyten zu deletieren. Dies geschah mittels eines Tamoxifen-induzierten Cre-Rekombinase-Gendeletionsmodells. Phänotypisch zeigten die Top2b-deletierten Mäuse 8 Wochen nach der Tamoxifen-Gabe signifikant reduzierte kardiale Ejektionsfraktionen sowie erhöhte linksventrikuläre enddiastolische und endsystolische Volumina. Weder Schlagvolumen noch Körpergewicht waren verändert. Die natriuretischen Peptide ANP und BNP waren in den Top2b-deletierten Tieren ebenfalls signifikant erhöht. Zusätzlich zeigten sowohl elektronenmikroskopische Untersuchungen als auch klassische histologische Verfahren fibrotische Veränderungen und erhöhte Kollagenablagerungen in Top2b-deletierten Tieren. Begleitend dazu stiegen die mRNA-Expressionslevel von Col1a1, Col3a1, Tgfβ1 und Tgfβ2 in den deletierten Tieren 8 Wochen nach der Implementierung der Deletion signifikant an. rnIn einer genomweiten Hochdurchsatz-Sequenzierung waren bereits 2 Wochen nach Tamoxifen-Gabe 128 Gene mindestens 2-fach gegenüber der Kontrollgruppe differentiell exprimiert. Eine genauere Analyse der veränderten Genexpression ließ bereits 14 Tage nach Implementierung der Deletion kardiale Verschlechterungen vermuten. So waren neben dem atrialen natriuretischen Peptid ANP die beiden häufigsten Kollagenarten im Herzen, Col3a1 und Col1a1, hochreguliert. rnInteressanterweise beinhalteten die 37 herunterregulierten Gene 11 Transkriptionsfaktoren. Da der Top2b in den letzten Jahren eine immer stärker werdende Bedeutung in der Transkription zugesprochen wird, sollte mittels Chromatin-Immunpräzipitation ein direkter Zusammenhang zwischen der Top2b-Deletion und der Herunterregulierung der 11 Transkriptionsfaktoren sowie die Bindung der Top2b an Promotoren ausgewählter, differentiell-exprimierter Gene untersucht werden. Generell konnte keine vermehrte Bindung von Top2b an Promotorbereiche gezeigt werden, was aber nicht dem generellen Fehlen einer Bindung gleichkommen muss. Vielmehr gab es methodische Schwierigkeiten, weshalb die Bedeutung der Top2b in der Transkription im Rahmen der vorliegenden Arbeit nicht ausreichend geklärt werden konnte.rnEine Kardiomyozyten-spezifische Top2b-Deletion mündete 8 Wochen nach Tamoxifen-Gabe in eine dilatative Kardiomyopathie. Zum gegenwärtigen Zeitpunkt sind keine klaren Aussagen zum zugrundeliegenden Mechanismus der entstehenden Herzschädigung in Folge einer Top2b-Deletion zu treffen. Es gibt jedoch Hinweise darauf, dass der Tumorsuppressormarker p53 eine wichtige Rolle in der Entstehung der dilatativen Kardiomyopathie spielen könnte. So konnte 8 Wochen nach der Top2b-Deletion mittels Chromatin-Immunpräzipitation eine erhöhte Bindung von p53 an Promotorregionen von…

Subjects/Keywords: Topoisomerase 2b; Kardiomyopathie; topoisomerase 2b; cardiomyopathy; Medical sciences Medicine

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Frensch, I. (2014). Die Rolle der Topoisomerase 2 beta in der normalen Herzfunktion sowie in der Entstehung der Herzinsuffizienz. (Doctoral Dissertation). Johannes Gutenberg Universität Mainz. Retrieved from http://ubm.opus.hbz-nrw.de/volltexte/2014/3900/

Chicago Manual of Style (16^th Edition):

Frensch, Isabelle. “Die Rolle der Topoisomerase 2 beta in der normalen Herzfunktion sowie in der Entstehung der Herzinsuffizienz.” 2014. Doctoral Dissertation, Johannes Gutenberg Universität Mainz. Accessed April 12, 2021. http://ubm.opus.hbz-nrw.de/volltexte/2014/3900/.

MLA Handbook (7^th Edition):

Frensch, Isabelle. “Die Rolle der Topoisomerase 2 beta in der normalen Herzfunktion sowie in der Entstehung der Herzinsuffizienz.” 2014. Web. 12 Apr 2021.

Vancouver:

Frensch I. Die Rolle der Topoisomerase 2 beta in der normalen Herzfunktion sowie in der Entstehung der Herzinsuffizienz. [Internet] [Doctoral dissertation]. Johannes Gutenberg Universität Mainz; 2014. [cited 2021 Apr 12]. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2014/3900/.

Council of Science Editors:

Frensch I. Die Rolle der Topoisomerase 2 beta in der normalen Herzfunktion sowie in der Entstehung der Herzinsuffizienz. [Doctoral Dissertation]. Johannes Gutenberg Universität Mainz; 2014. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2014/3900/

Vanderbilt University

14. Lindsey, Jr., Robert Hunter. Insights into the Catalytic Mechanism of Eukaryotic and Bacterial Type II Topoisomerases and the Actions of Topoisomerase II Poisons.

Degree: PhD, Biochemistry, 2015, Vanderbilt University

URL: http://hdl.handle.net/1803/10739

► Coordination between the N-terminal gate and the catalytic core of topoisomerase II allows the proper capture, cleavage, and transport of DNA during catalysis. Because the… (more)

▼ Coordination between the N-terminal gate and the catalytic core of topoisomerase II allows the proper capture, cleavage, and transport of DNA during catalysis. Because the activities of these domains are tightly linked, it has been difficult to discern their individual contributions to enzyme-DNA interactions and drug mechanism. To address the roles of these domains, the activity of the human topoisomerase IIα catalytic core was analyzed. The catalytic core and full-length enzyme both maintained higher levels of cleavage with negatively vs. positively supercoiled plasmid. Thus, the ability to distinguish supercoil handedness is embedded within the catalytic core. However, the catalytic core displayed little ability to cleave DNA substrates that did not intrinsically provide the enzyme with a transport segment (substrates that did not contain crossovers). Therefore, the N-terminal gate is critical for the capture of the T-segment. In contrast to interfacial topoisomerase II poisons, covalent poisons did not enhance DNA cleavage mediated by the catalytic core. This distinction allowed further characterization of etoposide quinone, a drug metabolite that acts primarily as a covalent poison. Etoposide quinone retained some ability to enhance DNA cleavage mediated by the catalytic core, indicating that it still can function as an interfacial poison. Gyrase removes positive supercoils ahead of replication forks in bacteria. However, nothing is known about the effects of supercoil geometry on DNA cleavage mediated by gyrase. Similar to the human type II enzymes, Bacillus anthracis gyrase could discern supercoil geometry, and maintained lower levels of cleavage complexes with positively supercoiled substrates. Interactions of quinolones with topoisomerase IV are mediated through a water-metal ion bridge that is anchored in part by a conserved serine residue (Ser81 B. anthracis gyrase). However, the role of the bridge appears to vary between species and has not been assessed in gyrase. Therefore, the sensitivity of wild-type and GyrAS85L gyrase towards quinolones and quinazolinediones was assessed. Preliminary findings support the hypothesis that gyrase uses the water-metal ion bridge to coordinate quinolone interactions and pave the way for future mechanistic studies. Advisors/Committee Members: Daniel Liebler (committee member), Martin Egli (committee member), Eric Skaar (committee member), Nicholas Reiter (committee member), Neil Osheroff (Committee Chair).

Subjects/Keywords: gyrase; DNA topology; topoisomerase II poisons; quinolones; topoisomerase II

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Lindsey, Jr., R. H. (2015). Insights into the Catalytic Mechanism of Eukaryotic and Bacterial Type II Topoisomerases and the Actions of Topoisomerase II Poisons. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10739

Chicago Manual of Style (16^th Edition):

Lindsey, Jr., Robert Hunter. “Insights into the Catalytic Mechanism of Eukaryotic and Bacterial Type II Topoisomerases and the Actions of Topoisomerase II Poisons.” 2015. Doctoral Dissertation, Vanderbilt University. Accessed April 12, 2021. http://hdl.handle.net/1803/10739.

MLA Handbook (7^th Edition):

Lindsey, Jr., Robert Hunter. “Insights into the Catalytic Mechanism of Eukaryotic and Bacterial Type II Topoisomerases and the Actions of Topoisomerase II Poisons.” 2015. Web. 12 Apr 2021.

Vancouver:

Lindsey, Jr. RH. Insights into the Catalytic Mechanism of Eukaryotic and Bacterial Type II Topoisomerases and the Actions of Topoisomerase II Poisons. [Internet] [Doctoral dissertation]. Vanderbilt University; 2015. [cited 2021 Apr 12]. Available from: http://hdl.handle.net/1803/10739.

Council of Science Editors:

Lindsey, Jr. RH. Insights into the Catalytic Mechanism of Eukaryotic and Bacterial Type II Topoisomerases and the Actions of Topoisomerase II Poisons. [Doctoral Dissertation]. Vanderbilt University; 2015. Available from: http://hdl.handle.net/1803/10739

15. Gouveia, Rawny Galdino. Síntese, caracterização estrutural e avaliação dos possíveis mecanismos de ação dos derivados espiro-acridínicos.

Degree: 2017, Universidade Estadual da Paraíba; Programa de Pós-Graduação em Ciências Farmacêuticas – PPGCF; UEPB; Brasil; Pró-Reitoria de Pós-Graduação e Pesquisa - PRPGP

URL: http://tede.bc.uepb.edu.br/jspui/handle/tede/2862

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Made available in DSpace on 2017-10-26T16:55:41Z (GMT). No. of bitstreams: 1 PDF - Rawny Galdino Gouveia.pdf: 21187770 bytes, checksum: 320540e5f560ea3cbfd7e23034f4444d (MD5) Previous issue date: 2017-02-24

Among the main alternatives for cancer treatment, chemotherapy is one of them, but most chemotherapeutic agents act nonspecifically, damaging several types of body cells. DNA intercalators are standout among the existing chemotherapeutics, for example, among these compounds, acridine derivatives have inhibitory activity against nuclear regulatory enzymes, such as topoisomerase, and there is a strong interaction with pairs of DNA bases. Therefore, researchers are seeking to find new candidates intercalators of DNA drugs and a significant number of molecules have been evaluated for their antitumor and intercalators properties. This paper proposed the synthesis of novel spiro-acridines derivatives; it was conducted to evaluate their interaction with BSA, DNA, and inhibition of the enzyme topoisomerase IIα. Thus, eleven new spiro-acridínicos compounds were synthesized and were determined their physicochemical characteristics and demonstrated the possible reaction mechanisms for obtaining these compounds. The compounds were obtained in parallel and convergent manner, initially the diphenylamine suffered an acylation followed by cyclization, leading to 9-metilacridina that by successive reactions led to 9-carboxaldehyde acridine. In parallel, 2- cianoacetohidrazina reacted with aromatic aldehydes substituted in acid and ethanol, leading to N-acylhydrazones intermediates substituted, finally, the two intermediates were condensed, through a Knovenagel reaction and suffered spontaneous cyclization, leading to spiro-acridine derivates. The compounds show yields ranging from 24% to 86.75%, and melting points ranging between 3 and 5 °C. Most of the compounds were characterized and had their chemical structures elucidated by spectroscopic H-NMR and C-NMR; IR and MS. By 1^H NMR analysis were observed singlets referring to NH, protons coming from the formation of the C = N bond (imino carbon) and C = C (vinyl carbon) corroborating the structural elucidation of all compounds. The 13^C NMR spectra showed the absorptions of carbon atoms characteristic of spiro-acridine derivatives, especially the chemical shift showed by the quaternary carbon evidenced on the signals from 69.33 to 71.59, demonstrating the occurrence of spontaneous cyclization of spiro-acridine derivatives. The compounds evaluated against the enzyme Topoisomerase IIα, presented different degrees of inhibition when compared with the mAMSA…

Advisors/Committee Members: Moura, Ricardo Olímpio de, Almeida, Sinara Mônica Vitalino de, Alves, Harley da Silva, Lafayette, Elizabeth Almeida.

Subjects/Keywords: Topoisomerase; Acridina; Quimioterápicos; Terapia antitumoral; Acridine; Topoisomerase; CIENCIAS DA SAUDE::FARMACIA

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gouveia, R. G. (2017). Síntese, caracterização estrutural e avaliação dos possíveis mecanismos de ação dos derivados espiro-acridínicos. (Masters Thesis). Universidade Estadual da Paraíba; Programa de Pós-Graduação em Ciências Farmacêuticas – PPGCF; UEPB; Brasil; Pró-Reitoria de Pós-Graduação e Pesquisa - PRPGP. Retrieved from http://tede.bc.uepb.edu.br/jspui/handle/tede/2862

Chicago Manual of Style (16^th Edition):

Gouveia, Rawny Galdino. “Síntese, caracterização estrutural e avaliação dos possíveis mecanismos de ação dos derivados espiro-acridínicos.” 2017. Masters Thesis, Universidade Estadual da Paraíba; Programa de Pós-Graduação em Ciências Farmacêuticas – PPGCF; UEPB; Brasil; Pró-Reitoria de Pós-Graduação e Pesquisa - PRPGP. Accessed April 12, 2021. http://tede.bc.uepb.edu.br/jspui/handle/tede/2862.

MLA Handbook (7^th Edition):

Gouveia, Rawny Galdino. “Síntese, caracterização estrutural e avaliação dos possíveis mecanismos de ação dos derivados espiro-acridínicos.” 2017. Web. 12 Apr 2021.

Vancouver:

Gouveia RG. Síntese, caracterização estrutural e avaliação dos possíveis mecanismos de ação dos derivados espiro-acridínicos. [Internet] [Masters thesis]. Universidade Estadual da Paraíba; Programa de Pós-Graduação em Ciências Farmacêuticas – PPGCF; UEPB; Brasil; Pró-Reitoria de Pós-Graduação e Pesquisa - PRPGP; 2017. [cited 2021 Apr 12]. Available from: http://tede.bc.uepb.edu.br/jspui/handle/tede/2862.

Council of Science Editors:

Gouveia RG. Síntese, caracterização estrutural e avaliação dos possíveis mecanismos de ação dos derivados espiro-acridínicos. [Masters Thesis]. Universidade Estadual da Paraíba; Programa de Pós-Graduação em Ciências Farmacêuticas – PPGCF; UEPB; Brasil; Pró-Reitoria de Pós-Graduação e Pesquisa - PRPGP; 2017. Available from: http://tede.bc.uepb.edu.br/jspui/handle/tede/2862

16. Nathalia de Campos Rodrigues. Estudo estrutural das enzimas Topoisomerase II Mitocondrial e Old Yellow Enzyme de Trypanosoma cruzi.

Degree: 2014, University of São Paulo

URL: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-24032014-151614/

►

Doenças tropicais negligenciadas compartilham características que permitem que elas persistam nas condições de pobreza, onde se aglomeram e se sobrepõe frequentemente. Mais de um bilhão… (more)

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Doenças tropicais negligenciadas compartilham características que permitem que elas persistam nas condições de pobreza, onde se aglomeram e se sobrepõe frequentemente. Mais de um bilhão de pessoas sofrem de uma ou mais doenças tropicais negligenciadas. Entre estas está a doença de Chagas, resultante da infecção pelo protozoário parasito hemoflagelado Trypanosoma cruzi, tendo insetos triatomíneos como vetores. Topoisomerases são enzimas envolvidas na regulação do superespiralamento do DNA resolvendo problemas topológicos associados com replicação, transcrição, recombinação e reparo. As topoisomerases do tipo II são essenciais para tripanossomatídeos por atuarem na replicação e organização do DNA contido em uma região especializada da mitocôndria denominada cinetoplasto. O estudo da Topoisomerase II Mitocondrial (TcTopoIImit) foi realizado através de análises sequenciais e estruturais de outras topoisomerases para a determinação de construções para a clonagem. As construções para o domínio N-terminal foram clonadas no vetor pTZ57R/T e subclonadas em vetores do sistema pET para expressão proteica em E. coli. Experimentos de expressão foram realizados em diferentes cepas, vetores, soluções tampão e outros parâmetros variáveis visando a obtenção dos produtos recombinantes na forma solúvel, porém, tais resultados não foram obtidos. A flavoproteína Old Yellow Enzyme de Trypanosoma cruzi (TcOYE) é uma oxidoredutase que usa NAD(P)H como cofator. Esta enzima é clinicamente relevante devido ao seu papel no mecanismo de ação de alguns agentes tripanocidas, utilizados no tratamento da doença de Chagas, por produzirem espécies reativas de oxigênio. Neste trabalho, a enzima recombinante TcOYE foi produzida, purificada, cristalizada pelo método de difusão de vapor e sua estrutura cristalográfica, resolvida por substituição molecular e refinada. A TcOYE foi cristalizada nas formas cristalinas P212121 e P21 e os dados de difração foram coletados para o máximo de resolução de 1,27 e 2,00 Å, respectivamente. As coordenadas atômicas e fatores de estrutura das estruturas da TcOYE nas formas cristalinas P212121 e P21 foram depositados no Banco de Dados de Proteínas com os códigos de acesso 4E2B e 4E2D, respectivamente. A TcOYE apresenta um enovelamento canônico em um barril (α/β)8 com o grupo prostético localizado na cavidade maior do sítio ativo. Após a obtenção dos modelos cristalográficos análises sequenciais e estruturais foram realizadas para a TcOYE e outras OYEs. A região 141-156 do subdomínio capping em TcOYE, assim como em outras OYEs, é intrinsecamente desestruturada exibindo altos valores de fatores B. A região mais divergente entre as OYEs é o loop estendido (289-297), que pode variar em comprimento e composição mudando o volume e a acessibilidade ao sítio ativo.

Neglected tropical diseases share features that allow them to persist in conditions of poverty, which clump together and frequently overlap. More than 1 billion people suffer from one or more neglected tropical diseases. Among them is the…

Advisors/Committee Members: Glaucius Oliva, Marcio Vinicius Bertacine Dias, Marcos Roberto de Mattos Fontes, Humberto D\'Muniz Pereira, Ariel Mariano Silber.

Subjects/Keywords: Trypanosoma cruzi; Cristalografia de proteínas; Topoisomerase; Trypanosoma cruzi; Protein crystallography; Topoisomerase

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Rodrigues, N. d. C. (2014). Estudo estrutural das enzimas Topoisomerase II Mitocondrial e Old Yellow Enzyme de Trypanosoma cruzi. (Doctoral Dissertation). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/76/76132/tde-24032014-151614/

Chicago Manual of Style (16^th Edition):

Rodrigues, Nathalia de Campos. “Estudo estrutural das enzimas Topoisomerase II Mitocondrial e Old Yellow Enzyme de Trypanosoma cruzi.” 2014. Doctoral Dissertation, University of São Paulo. Accessed April 12, 2021. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-24032014-151614/.

MLA Handbook (7^th Edition):

Rodrigues, Nathalia de Campos. “Estudo estrutural das enzimas Topoisomerase II Mitocondrial e Old Yellow Enzyme de Trypanosoma cruzi.” 2014. Web. 12 Apr 2021.

Vancouver:

Rodrigues NdC. Estudo estrutural das enzimas Topoisomerase II Mitocondrial e Old Yellow Enzyme de Trypanosoma cruzi. [Internet] [Doctoral dissertation]. University of São Paulo; 2014. [cited 2021 Apr 12]. Available from: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-24032014-151614/.

Council of Science Editors:

Rodrigues NdC. Estudo estrutural das enzimas Topoisomerase II Mitocondrial e Old Yellow Enzyme de Trypanosoma cruzi. [Doctoral Dissertation]. University of São Paulo; 2014. Available from: http://www.teses.usp.br/teses/disponiveis/76/76132/tde-24032014-151614/

17. Edson Fernandes da Silva. Síntese, determinação de parâmetros físico-químicos e avaliação biológica in Vivivo e in Vitro de compostos da classe 1,3,4-Tiadiazólio.

Degree: 2007, Universidade Federal Rural do Rio de Janeiro

URL: http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=960 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=959

►

Mesoionic compounds are heterocycles with dipolar structure. They have been considered interesting because of their several biological activities and other applications, such as new materials… (more)

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Mesoionic compounds are heterocycles with dipolar structure. They have been considered interesting because of their several biological activities and other applications, such as new materials and dyes. In this work were synthesized 17 salts of mesoionic compounds from the 1,3,4- thiadiazolium-2-aminide class, in which 7 are new compounds. The synthetic methodology involved the anhydroacylation reaction of 1,4-thiosemicarbazide with substituted cinnamoyl chlorides. These compounds were characterized by spectroscopic techniques such NMR 1H, 13C and infrared. Chemosensitivity assays against Ehrlich carcinoma cells showed significant cytotoxic activity for mesoionic salts, and the 4-OEt derivative was the most active synthesized compound. The mesoionic compounds had been assayed with DNA-topoisomerases I and IIα enzymes, several derivatives showed inhibitory activity especially on DNA-topoisomerase IIα. Very promising and satisfactory results were observed for chloro and fluor-derivatives when the in vivo anti-tumour activity was evaluated on mice with Ehrlich carcinoma. The physico-chemical parameters were determined to aim the quantitative-structure relationship (QSAR) study. The hydrophobic parameter, log k, was experimentally determined for mesoionic compounds using the high performance liquid chromatography (HPLC) method. The electronic theoretical parameters were calculated using semi-empirical molecular orbital methods for all series derivatives. Their structures were optimized using the MOPAC 6.0 package and PM3 Hamiltonian. The mesoionic salts (14) were also assayed in vitro against Leishmania amazonensis in Laboratório de Bioquímica de Tripanossomatideos FIOCRUZ, and very promising results for leishmaniasis chemotherapy have been observed. The QSAR study indicated that the hydrophobic parameters (log k and π) and resonance electronic effect (R) were the most significant contribution to the cytotoxic activity.

Os compostos mesoiônicos são heterociclos com estrutura dipolar. Esses compostos têm apresentado bastante interesse devido à sua diversificada atividade biológica, e também por sua utilização como novos materiais e corantes, entre outras. Neste trabalho de tese foram sintetizados 17 sais de compostos mesoiônicos da classe 1,3,4-tiadiazólio, sendo 7 novos. A metodologia utilizada envolveu a reação de acilação anidra da 1,4-difenil-tiossemicarbazida na presença de cloretos de cinamoíla-substituídos. Esses compostos foram caracterizados por técnicas espectroscópicas, como RMN de 1H e 13C e infravermelho. Ensaios de quimiossensibilidade frente a células do carcinoma de Ehrlich foram realizados, indicando significativa atividade citotóxica para os sais dos compostos mesoiônicos, sendo o mais ativo o 4-OEt-substituído dentre aqueles sintetizados neste trabalho. Os mesoiônicos sintetizados foram submetidos à ensaios com as enzimas DNAtopoisomerases I e II-α, onde vários mostraram-se inibidores das mesmas, principalmente em relação a Topo II-α. Avaliou-se, também, a atividade…

Advisors/Committee Members: Áurea Echevarria Aznar N. Lima, Noema Faiga Grynberg.

Subjects/Keywords: mesoiônicos; 1,3,4-Tiadiazólio; Topoisomerase; QUIMICA ORGANICA

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Silva, E. F. d. (2007). Síntese, determinação de parâmetros físico-químicos e avaliação biológica in Vivivo e in Vitro de compostos da classe 1,3,4-Tiadiazólio. (Thesis). Universidade Federal Rural do Rio de Janeiro. Retrieved from http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=960 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=959

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Silva, Edson Fernandes da. “Síntese, determinação de parâmetros físico-químicos e avaliação biológica in Vivivo e in Vitro de compostos da classe 1,3,4-Tiadiazólio.” 2007. Thesis, Universidade Federal Rural do Rio de Janeiro. Accessed April 12, 2021. http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=960 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=959.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Silva, Edson Fernandes da. “Síntese, determinação de parâmetros físico-químicos e avaliação biológica in Vivivo e in Vitro de compostos da classe 1,3,4-Tiadiazólio.” 2007. Web. 12 Apr 2021.

Vancouver:

Silva EFd. Síntese, determinação de parâmetros físico-químicos e avaliação biológica in Vivivo e in Vitro de compostos da classe 1,3,4-Tiadiazólio. [Internet] [Thesis]. Universidade Federal Rural do Rio de Janeiro; 2007. [cited 2021 Apr 12]. Available from: http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=960 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=959.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Silva EFd. Síntese, determinação de parâmetros físico-químicos e avaliação biológica in Vivivo e in Vitro de compostos da classe 1,3,4-Tiadiazólio. [Thesis]. Universidade Federal Rural do Rio de Janeiro; 2007. Available from: http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=960 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=959

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Vanderbilt University

18. Aldred, Katie June. Mechanism of Quinolone Action and Resistance in Bacterial and Human Type II Topoisomerases.

Degree: PhD, Biochemistry, 2014, Vanderbilt University

URL: http://hdl.handle.net/1803/10694

► Quinolones are the most commonly prescribed antibacterials worldwide; however, their clinical utility is threatened by the rising occurrence of resistance. Quinolones kill bacterial cells by… (more)

▼ Quinolones are the most commonly prescribed antibacterials worldwide; however, their clinical utility is threatened by the rising occurrence of resistance. Quinolones kill bacterial cells by increasing the level of DNA breaks generated by the type II topoisomerases gyrase and topoisomerase IV. Target-mediated resistance, which occurs as point mutations in the target topoisomerases, is the most common and clinically significant form of resistance. Although mutations at a specific, highly conserved serine and acidic amino acid residue have long been known to cause quinolone resistance, the mechanism by which these enzyme alterations decrease drug activity has not been previously understood. The research described in this dissertation demonstrates that the primary interaction between clinically relevant quinolones and topoisomerase IV is mediated through a water-metal ion bridge anchored to the enzyme by the conserved serine and acidic residues. Mutations at these two residues, which are the most common alterations seen in quinolone-resistant bacterial strains, cause resistance by disrupting the water-metal ion bridge interaction. Based on results with a Gram-positive and a Gram-negative topoisomerase IV, it appears that the water-metal ion bridge may be a universal mechanism of quinolone-enzyme interaction. Because this interaction is formed with the drug core, it also explains the tolerance for structurally diverse substituents. Human topoisomerase IIα is resistant to clinically relevant quinolones because it cannot form the water-metal ion bridge. Quinolones and quinazolinediones that overcome resistance mutations in the bacterial type II enzymes do so by forming novel interactions through their C7 substituents, which can also form interactions with the human enzyme and give undesirable cross-reactivity. However, structure-activity relationship studies indicate that there are differences between the human and bacterial type II topoisomerases that can be sensed at the C7, C8, and N3 positions. Thus, it should be possible to design a quinolone or quinolone-like drug that overcomes the most common forms of target-mediated resistance without cross-reacting with the human enzymes. In addition, it may be possible to develop specific quinolones as anticancer agents. Advisors/Committee Members: Chuck Sanders (committee member), Eric Skaar (committee member), Fred Guengerich (committee member), Kathy Friedman (committee member), Neil Osheroff (Committee Chair).

Subjects/Keywords: water-metal ion bridge; quinolone; resistance; topoisomerase

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Aldred, K. J. (2014). Mechanism of Quinolone Action and Resistance in Bacterial and Human Type II Topoisomerases. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10694

Chicago Manual of Style (16^th Edition):

Aldred, Katie June. “Mechanism of Quinolone Action and Resistance in Bacterial and Human Type II Topoisomerases.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed April 12, 2021. http://hdl.handle.net/1803/10694.

MLA Handbook (7^th Edition):

Aldred, Katie June. “Mechanism of Quinolone Action and Resistance in Bacterial and Human Type II Topoisomerases.” 2014. Web. 12 Apr 2021.

Vancouver:

Aldred KJ. Mechanism of Quinolone Action and Resistance in Bacterial and Human Type II Topoisomerases. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Apr 12]. Available from: http://hdl.handle.net/1803/10694.

Council of Science Editors:

Aldred KJ. Mechanism of Quinolone Action and Resistance in Bacterial and Human Type II Topoisomerases. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/10694

University of Hyderabad

19. Konuru, Neelima. A study on the age dependent changes of topoisomerase ii a and topoisomerase ii isoforms in rat brain and sensitivity of topoisomerase ii isoforms to topo ii poisons; -.

Degree: Biochemistry, 2014, University of Hyderabad

URL: http://shodhganga.inflibnet.ac.in/handle/10603/25857

None

References p.86-93

Advisors/Committee Members: Kondapi, Anand K.

Subjects/Keywords: Biochemistry; Topoisomerase; Etoposide

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APA (6^th Edition):

Konuru, N. (2014). A study on the age dependent changes of topoisomerase ii a and topoisomerase ii isoforms in rat brain and sensitivity of topoisomerase ii isoforms to topo ii poisons; -. (Thesis). University of Hyderabad. Retrieved from http://shodhganga.inflibnet.ac.in/handle/10603/25857

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Konuru, Neelima. “A study on the age dependent changes of topoisomerase ii a and topoisomerase ii isoforms in rat brain and sensitivity of topoisomerase ii isoforms to topo ii poisons; -.” 2014. Thesis, University of Hyderabad. Accessed April 12, 2021. http://shodhganga.inflibnet.ac.in/handle/10603/25857.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Konuru, Neelima. “A study on the age dependent changes of topoisomerase ii a and topoisomerase ii isoforms in rat brain and sensitivity of topoisomerase ii isoforms to topo ii poisons; -.” 2014. Web. 12 Apr 2021.

Vancouver:

Konuru N. A study on the age dependent changes of topoisomerase ii a and topoisomerase ii isoforms in rat brain and sensitivity of topoisomerase ii isoforms to topo ii poisons; -. [Internet] [Thesis]. University of Hyderabad; 2014. [cited 2021 Apr 12]. Available from: http://shodhganga.inflibnet.ac.in/handle/10603/25857.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Konuru N. A study on the age dependent changes of topoisomerase ii a and topoisomerase ii isoforms in rat brain and sensitivity of topoisomerase ii isoforms to topo ii poisons; -. [Thesis]. University of Hyderabad; 2014. Available from: http://shodhganga.inflibnet.ac.in/handle/10603/25857

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Boston University

20. Unan, Elizabeth Claire. BRCA1 E3 ligase inhibitors induces synthetic lethality in CPT resistant cells.

Degree: MS, Medical Sciences, 2018, Boston University

URL: http://hdl.handle.net/2144/30867

► Camptothecin and its analogues (CPTs) represent one of the most potent classes of anticancer drugs used to treat several solid tumors. CPTs bind topoisomerase I… (more)

Subjects/Keywords: Oncology; BRCA1; Camptothecin; Topoisomerase; E3 ligase

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APA (6^th Edition):

Unan, E. C. (2018). BRCA1 E3 ligase inhibitors induces synthetic lethality in CPT resistant cells. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/30867

Chicago Manual of Style (16^th Edition):

Unan, Elizabeth Claire. “BRCA1 E3 ligase inhibitors induces synthetic lethality in CPT resistant cells.” 2018. Masters Thesis, Boston University. Accessed April 12, 2021. http://hdl.handle.net/2144/30867.

MLA Handbook (7^th Edition):

Unan, Elizabeth Claire. “BRCA1 E3 ligase inhibitors induces synthetic lethality in CPT resistant cells.” 2018. Web. 12 Apr 2021.

Vancouver:

Unan EC. BRCA1 E3 ligase inhibitors induces synthetic lethality in CPT resistant cells. [Internet] [Masters thesis]. Boston University; 2018. [cited 2021 Apr 12]. Available from: http://hdl.handle.net/2144/30867.

Council of Science Editors:

Unan EC. BRCA1 E3 ligase inhibitors induces synthetic lethality in CPT resistant cells. [Masters Thesis]. Boston University; 2018. Available from: http://hdl.handle.net/2144/30867

University of Iowa

21. Towle, Tyrell Robert. Synthesis of novel fluoroquinolone derivatives toward understanding aspects of function.

Degree: PhD, Pharmacy, 2013, University of Iowa

URL: https://ir.uiowa.edu/etd/5664

► Fluoroquinolones are broad spectrum antibiotics that have been in use for nearly 50 years. These agents are used to treat a variety of bacterial… (more)

▼ Fluoroquinolones are broad spectrum antibiotics that have been in use for nearly 50 years. These agents are used to treat a variety of bacterial infections from simple urinary tract infections to tuberculosis. The protein targets of fluoroquinolones are bacterial type II topoisomerases. Fluoroquinolones inhibit the function of these topoisomerases by intercalating in the nick site of the DNA and forming an interaction with helix-4 of the enzyme through a magnesium-water bridge. The binding of a fluoroquinolone stabilizes the DNA-topoisomerase-fluoroquinolone ternary complex. Helix-4 is where some of the most important fluoroquinolone resistance mutations occur. While the fluoroquinolone class of antibiotics has been successful at treating a variety of infections over the past few decades, a number of problems exist. These problems include the inability of many fluoroquinolones to kill non-growing cells, the emergence of fluoroquinolone resistant mutants, and adverse side effects of this antibiotic class. Thus, various aspects of fluoroquinolone structure and activity are explored in this study. The first topic explored is the question of what structural features are necessary for a fluoroquinolone to be able to kill bacteria in the presence and absence of the protein synthesis inhibitor, chloramphenicol (to mimic a dormant, non-growing state of the bacteria). Previous studies have shown that steric bulk at the C-8 position (especially a methoxy group) is necessary to support the ability of a fluoroquinolone to kill non-growing cells. In this study, the N-1 position of a series of C-8 methoxy fluoroquinolones was explored to gain an understanding of what substituents at the N-1 position of C-8 methoxy fluoroquinolones support the ability to rapidly kill bacteria in the presence of a protein synthesis inhibitor. In a second study the N-1 position is further explored, but with different goals. A recent crystal structure of a fluoroquinolone bound in the ternary complex with topoisomerase IV and DNA has revealed that the N-1 position of the fluoroquinolone is near in space to the catalytic tyrosine residue. It was reasoned that new interactions can be made with active site tyrosine residue through the N-1 position of the fluoroquinolone core. A number of N-1 fluoroquinolone derivatives were designed, synthesized, and evaluated for their ability to inhibit the DNA supercoiling activity of DNA gyrase, as well as the poisoning ability of the fluoroquinolones. The advantages of targeting the catalytic tyrosine residue are that this amino acid cannot be mutated without loss of enzyme function, and that by forming a new binding contact to the enzyme, activity can be maintained against helix-4 mutants. Finally, in a step toward the goal of mitigating the tendon related side effects of fluoroquinolones (thought to be due to Ca2+ coordination), the metal binding domain of the fluoroquinolone was altered. These fluoroquinolones were tested for their ability to inhibit and poison DNA gyrase. … Advisors/Committee Members: Kerns, Robert J. (supervisor).

Subjects/Keywords: Fluoroquinolone; Gyrase; Topoisomerase; Pharmacy and Pharmaceutical Sciences

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APA (6^th Edition):

Towle, T. R. (2013). Synthesis of novel fluoroquinolone derivatives toward understanding aspects of function. (Doctoral Dissertation). University of Iowa. Retrieved from https://ir.uiowa.edu/etd/5664

Chicago Manual of Style (16^th Edition):

Towle, Tyrell Robert. “Synthesis of novel fluoroquinolone derivatives toward understanding aspects of function.” 2013. Doctoral Dissertation, University of Iowa. Accessed April 12, 2021. https://ir.uiowa.edu/etd/5664.

MLA Handbook (7^th Edition):

Towle, Tyrell Robert. “Synthesis of novel fluoroquinolone derivatives toward understanding aspects of function.” 2013. Web. 12 Apr 2021.

Vancouver:

Towle TR. Synthesis of novel fluoroquinolone derivatives toward understanding aspects of function. [Internet] [Doctoral dissertation]. University of Iowa; 2013. [cited 2021 Apr 12]. Available from: https://ir.uiowa.edu/etd/5664.

Council of Science Editors:

Towle TR. Synthesis of novel fluoroquinolone derivatives toward understanding aspects of function. [Doctoral Dissertation]. University of Iowa; 2013. Available from: https://ir.uiowa.edu/etd/5664

Indian Institute of Science

22. Bakshi, Rahul P. Developmental And Functional Regulation Of DNA Topoisomerase II in Postnatal Rat Testis.

Degree: PhD, Faculty of Science, 2005, Indian Institute of Science

URL: http://etd.iisc.ac.in/handle/2005/166

► Characterization of the polyoma virus chromosome as a circular, double-stranded, supercoiled DNA (Weil and Vinograd, 1963; Vinograd et al.,-1965) made it apparent that the DNA… (more)

Subjects/Keywords: Biochemistry; DNA Topoisomerase

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APA (6^th Edition):

Bakshi, R. P. (2005). Developmental And Functional Regulation Of DNA Topoisomerase II in Postnatal Rat Testis. (Doctoral Dissertation). Indian Institute of Science. Retrieved from http://etd.iisc.ac.in/handle/2005/166

Chicago Manual of Style (16^th Edition):

Bakshi, Rahul P. “Developmental And Functional Regulation Of DNA Topoisomerase II in Postnatal Rat Testis.” 2005. Doctoral Dissertation, Indian Institute of Science. Accessed April 12, 2021. http://etd.iisc.ac.in/handle/2005/166.

MLA Handbook (7^th Edition):

Bakshi, Rahul P. “Developmental And Functional Regulation Of DNA Topoisomerase II in Postnatal Rat Testis.” 2005. Web. 12 Apr 2021.

Vancouver:

Bakshi RP. Developmental And Functional Regulation Of DNA Topoisomerase II in Postnatal Rat Testis. [Internet] [Doctoral dissertation]. Indian Institute of Science; 2005. [cited 2021 Apr 12]. Available from: http://etd.iisc.ac.in/handle/2005/166.

Council of Science Editors:

Bakshi RP. Developmental And Functional Regulation Of DNA Topoisomerase II in Postnatal Rat Testis. [Doctoral Dissertation]. Indian Institute of Science; 2005. Available from: http://etd.iisc.ac.in/handle/2005/166

Massey University

23. Magan, Natisha. Basal transcription of human topoisomerase II.

Degree: MS, Biochemistry, 2002, Massey University

URL: http://hdl.handle.net/10179/11575

► Topoisomerase II is a ubiquitously expressed enzyme, which is required for cell survival. It has the ability to alter the topological states of DNA by… (more)

▼ Topoisomerase II is a ubiquitously expressed enzyme, which is required for cell survival. It has the ability to alter the topological states of DNA by introducing transient double-stranded breaks in DNA. Humans have two topoisomerase II isoforms, ɑ and β, and both are differentially expressed and localized. Tissues with rapidly proliferating cells exhibit elevated topoisomerase IIɑ gene expression whereas the β isoform is ubiquitously expressed amongst tissues. In addition to a role in cell survival, a number of anti-cancer drugs have been shown to target human topoisomerase II in vivo. However, the development of drug resistance is a major clinical problem; for example, approximately 60% of breast cancers treated with the topoisomerase II poison doxorubicin become resistant to this drug. Down-regulation of topoisomerase II is thought to be one of the factors involved in the development of drug resistance, where the relative levels of topoisomerase IIɑ and topoisomerase IIβ in cells is thought to effect drug efficacy. The expression of topoisomerase IIɑ and β is regulated at the transcriptional level, through binding of transcription factors to specific elements within the promoter sequence. Therefore investigating the transcriptional regulation of both isoforms could lead to an understanding of the mechanisms involved in the development of drug resistance. The initial aim of this study was to isolate a fragment of the upstream regulatory sequence of the topoisomerase IIβ gene and carry out systematic analysis of this sequence. However, this could not be pursued, as the clones that were examined did not contain the required topoisomerase IIβ sequence. This study progressed to examine the relevance of three elements (GC1, ICB1 and GC2) within the topoisomerase IIɑ minimal promoter and the importance of the cognate transcription factors NF-Y, Spl and Sp3 in regulating the expression of the topoisomerase IIɑ gene. Electrophoretic mobility shift assays and transient transfection assays were used to study protein/DNA interactions and the functional significance of these interactions, respectively. Both NF-Y and Spl were shown to activate the transcriptional regulation of topoisomerase IIɑ by binding to their respective elements; in addition functional interactions between the two proteins bound to the promoter was observed.

Subjects/Keywords: DNA topoisomerase II

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APA (6^th Edition):

Magan, N. (2002). Basal transcription of human topoisomerase II. (Masters Thesis). Massey University. Retrieved from http://hdl.handle.net/10179/11575

Chicago Manual of Style (16^th Edition):

Magan, Natisha. “Basal transcription of human topoisomerase II.” 2002. Masters Thesis, Massey University. Accessed April 12, 2021. http://hdl.handle.net/10179/11575.

MLA Handbook (7^th Edition):

Magan, Natisha. “Basal transcription of human topoisomerase II.” 2002. Web. 12 Apr 2021.

Vancouver:

Magan N. Basal transcription of human topoisomerase II. [Internet] [Masters thesis]. Massey University; 2002. [cited 2021 Apr 12]. Available from: http://hdl.handle.net/10179/11575.

Council of Science Editors:

Magan N. Basal transcription of human topoisomerase II. [Masters Thesis]. Massey University; 2002. Available from: http://hdl.handle.net/10179/11575

Massey University

24. Willingham, Melanie. Regulation of the human topoisomerase IIℓ: a thesis presented to Massey University in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry .

Degree: 2004, Massey University

URL: http://hdl.handle.net/10179/13466

► Eukaryotic DNA topoisomcrase II is a ubiquitous nuclear enzyme essential for maintaining the correct conformation of DNA. The enzyme acts to catalyse changes in the… (more)

▼ Eukaryotic DNA topoisomcrase II is a ubiquitous nuclear enzyme essential for maintaining the correct conformation of DNA. The enzyme acts to catalyse changes in the tertian structure of DNA. via the introduction of transient double-stranded breaks. Mammalian cells express two isoforms of type II topoisomerase. designated topoisomerase IIα and topoisomerase IIβ, which display differential expression and intracellular localisation. Levels of topoisomerase IIα gene expression are elevated in rapidly proliferating cells, whereas the β isoform is expressed at approximately equal levels throughout the cell cycle. Protein products of the two isoforms of topoisomerase II found in human cells are the primary intracellular targets of many common, effective chemotherapy drugs. The development of drug resistance, however, is a major clinical problem caused by both enzymes. The levels of topoisomerase IIα and topoisomerase IIβ are important determinants for the sensitivity of cells to the cytoxicity of drugs, with down-regulation of topoisomerase II thought to be a major factor involved in drug resistance. The rate of transcription is the main mechanism for controlling topoisomerase II expression and activity, and this is achieved by the binding of transcription factors to specific regulatory elements within the promoter sequence. Molecular mechanisms responsible for the regulation of expression of the topoisomerase II enzymes are thought to be associated with resistance to chemotherapy drugs, and therefore understanding these mechanisms is an important research focus. This study reports the cloning and characterisation of a 1.5 kb fragment of the 5'- flanking and untranslated region of the topoisomerase IIβ promoter (-1357 to +122). Analyses of 5'-serially and internally deleted lueiferase reporter constructs revealed a region upstream of the transcription start site (-1357 to -1228). which could have a negative regulatory role, and suggested 55% of topoisomerase IIβ promoter activity could be attributed to the region between -654 and -456. Mutational analysis of putative regulatory elements indicated that the two inverted CCAAT box (ICB1 and ICB2) within the latter region were important for regulation of topoisomerase IIβ promoter activity. Gel mobility shift assays indicated that both inverted CCAAT boxes in the promoter bound the transcription factor NF-Y. while ICB2 and a GC element were capable of binding transcription factors Sp1 and Sp3.

Subjects/Keywords: DNA topoisomerase II

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APA (6^th Edition):

Willingham, M. (2004). Regulation of the human topoisomerase IIℓ: a thesis presented to Massey University in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry . (Thesis). Massey University. Retrieved from http://hdl.handle.net/10179/13466

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Willingham, Melanie. “Regulation of the human topoisomerase IIℓ: a thesis presented to Massey University in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry .” 2004. Thesis, Massey University. Accessed April 12, 2021. http://hdl.handle.net/10179/13466.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Willingham, Melanie. “Regulation of the human topoisomerase IIℓ: a thesis presented to Massey University in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry .” 2004. Web. 12 Apr 2021.

Vancouver:

Willingham M. Regulation of the human topoisomerase IIℓ: a thesis presented to Massey University in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry . [Internet] [Thesis]. Massey University; 2004. [cited 2021 Apr 12]. Available from: http://hdl.handle.net/10179/13466.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Willingham M. Regulation of the human topoisomerase IIℓ: a thesis presented to Massey University in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry . [Thesis]. Massey University; 2004. Available from: http://hdl.handle.net/10179/13466

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Massey University

25. Hintz, Patricia Ann. The role of NF-Y in the transcriptional regulation of human topoisomerase II¯ : a thesis presented to Massey University in partial fulfilment of the requirement for the degree of Master of Science in Biochemistry .

Degree: 2001, Massey University

URL: http://hdl.handle.net/10179/13521

► DNA topoisomerases are ubiquitous enzymes that catalyse reactions that alter the topological state of DNA during the various processes of DNA metabolism including transcription, recombination,… (more)

▼ DNA topoisomerases are ubiquitous enzymes that catalyse reactions that alter the topological state of DNA during the various processes of DNA metabolism including transcription, recombination, replication and chromosome segregation. Human cells exhibit a Type II enzyme termed DNA topoisomerase IIα. This enzyme is expressed at higher levels in proliferating cells due to an increased demand for chromosome separation. This is advantageous with respect to some of the drugs used in chemotherapy. These drugs can specifically target cancer cells by only being effective at high levels of topoisomerase IIα gene expression. However, the use of such drugs has been limited by both toxicity and the development of resistance. This resistance has been associated with a decrease in topoisomerase IIα at both protein and mRNA levels. The topoisomerase Ila minimal promoter is 650 base pairs in length and includes promoter elements such as inverted CCAAT boxes (ICBs) and GC rich regions. It has been determined that the ICB elements are of the most interest in terms of regulation of the topoisomerase IIα gene expression. Several studies have shown that the transcription factor NF-Y binds to ICB1-4 of the topoisomerase IIα promoter and regulates transcription through these elements. This study aimed to determine the importance of NF-Y in the transcriptional regulation of topoisomerase IIα and to investigate the molecular mechanisms by which NF-Y associates with the topoisomerase IIα promoter with a particular focus on the inverted CCAAT box elements. The binding of NF-Y to oligonucleotides containing selected consensus elements of the topoisomerase IIα promoter was analysed (in vitro) by electrophoretic mobility shift binding assays. The importance of NF-Y in the regulation of topoisomerase IIα expression was analysed by functional assays, using reporter gene constructs in transiently transfected HeLa cells. The binding studies indicated that the flanking sequences affect the affinity of the transcription factor NF-Y for ICB1 and ICB2 and that a regulatory element flanking ICB2 may aid in NF-Y binding to that element. Functional assays showed that NF-Y appears to act a negative regulator of topoisomerase IIα with its effect being entirely -due to interaction with ICB2.

Subjects/Keywords: DNA topoisomerase II

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APA (6^th Edition):

Hintz, P. A. (2001). The role of NF-Y in the transcriptional regulation of human topoisomerase II¯ : a thesis presented to Massey University in partial fulfilment of the requirement for the degree of Master of Science in Biochemistry . (Thesis). Massey University. Retrieved from http://hdl.handle.net/10179/13521

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Hintz, Patricia Ann. “The role of NF-Y in the transcriptional regulation of human topoisomerase II¯ : a thesis presented to Massey University in partial fulfilment of the requirement for the degree of Master of Science in Biochemistry .” 2001. Thesis, Massey University. Accessed April 12, 2021. http://hdl.handle.net/10179/13521.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Hintz, Patricia Ann. “The role of NF-Y in the transcriptional regulation of human topoisomerase II¯ : a thesis presented to Massey University in partial fulfilment of the requirement for the degree of Master of Science in Biochemistry .” 2001. Web. 12 Apr 2021.

Vancouver:

Hintz PA. The role of NF-Y in the transcriptional regulation of human topoisomerase II¯ : a thesis presented to Massey University in partial fulfilment of the requirement for the degree of Master of Science in Biochemistry . [Internet] [Thesis]. Massey University; 2001. [cited 2021 Apr 12]. Available from: http://hdl.handle.net/10179/13521.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Hintz PA. The role of NF-Y in the transcriptional regulation of human topoisomerase II¯ : a thesis presented to Massey University in partial fulfilment of the requirement for the degree of Master of Science in Biochemistry . [Thesis]. Massey University; 2001. Available from: http://hdl.handle.net/10179/13521

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of New South Wales

26. Drwal, Malgorzata N. Design of novel inhibitors of DNA topoisomerases using computer-aided methods.

Degree: Medical Sciences, 2013, University of New South Wales

URL: http://handle.unsw.edu.au/1959.4/52732 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:11405/SOURCE01?view=true

► Humans possess two main types of topoisomerase (Top) enzymes, Top1 and Top2, which have different structures and mechanisms of action. Both Top1 and Top2 are… (more)

▼ Humans possess two main types of topoisomerase (Top) enzymes, Top1 and Top2, which have different structures and mechanisms of action. Both Top1 and Top2 are over-expressed in tumour cells and therefore important targets in anticancer therapy. Several topoisomerase inhibitors are used clinically. However, their use is limited due to side effects and drug resistance. Hence, the search for novel Top inhibitors is ongoing. In particular, the development of dual Top1/Top2 inhibitors is believed to be associated with advantageous drugs displaying improved anticancer activity and reduced drug resistance problems.This study reports the use of computer-aided drug design methods to discover novel Top1, Top2 and dual inhibitors. In particular, available ligand and crystal structure information was analysed and used to develop ligand- and complex-based pharmacophores which were applied in database screening of the National Cancer Institute (NCI, USA) database. To filter the hits obtained, docking, 2D-similarity methods, druglikeness filters and expert selection were used. Structurally novel potential Top1 and Top2 inhibitors were identified by the study and, in case of Top1, the activity of the hits was confirmed in in vitro enzyme inhibition and cytotoxicity assays performed at the National Cancer Institute (USA). Furthermore, the performance of the developed pharmacophores and the docking protocols used was evaluated in a retrospective analysis based on selected test set compounds. As an alternative approach, pharmacophore models for Top1 were also generated in a purely structure-based manner, based on binding pocket interaction maps. Different approaches to cluster and select pharmacophore features were investigated, including hierarchical clustering methods, energy calculations and the use of pharmacophore subsets. In addition, the performance of structure-based pharmacophores was investigated in prospective and retrospective analyses. In the final part of the study, all methods developed for Top1 and Top2 were combined to suggest novel dual topoisomerase inhibitors.In conclusion, this study presents the application of computer-aided drug design techniques which led to the identification of structurally novel Top1, Top2 and dual inhibitors worthy of further investigation as potential anticancer agents. Advisors/Committee Members: Griffith, Renate, Medical Sciences, Faculty of Medicine, UNSW, Wakelin, Laurence, Medical Sciences, Faculty of Medicine, UNSW.

Subjects/Keywords: Computer-aided drug design; DNA topoisomerase inhibitors

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Drwal, M. N. (2013). Design of novel inhibitors of DNA topoisomerases using computer-aided methods. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/52732 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:11405/SOURCE01?view=true

Chicago Manual of Style (16^th Edition):

Drwal, Malgorzata N. “Design of novel inhibitors of DNA topoisomerases using computer-aided methods.” 2013. Doctoral Dissertation, University of New South Wales. Accessed April 12, 2021. http://handle.unsw.edu.au/1959.4/52732 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:11405/SOURCE01?view=true.

MLA Handbook (7^th Edition):

Drwal, Malgorzata N. “Design of novel inhibitors of DNA topoisomerases using computer-aided methods.” 2013. Web. 12 Apr 2021.

Vancouver:

Drwal MN. Design of novel inhibitors of DNA topoisomerases using computer-aided methods. [Internet] [Doctoral dissertation]. University of New South Wales; 2013. [cited 2021 Apr 12]. Available from: http://handle.unsw.edu.au/1959.4/52732 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:11405/SOURCE01?view=true.

Council of Science Editors:

Drwal MN. Design of novel inhibitors of DNA topoisomerases using computer-aided methods. [Doctoral Dissertation]. University of New South Wales; 2013. Available from: http://handle.unsw.edu.au/1959.4/52732 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:11405/SOURCE01?view=true

27. Delarmelina, Maicon. Síntese, avaliação biológica e docking de novos derivados 2,3-substituídos-1,4-naftoquinônicos contendo nitrogênio, oxigênio e enxofre com atividade anticâncer.

Degree: 2013, Universidade Federal do Espírito Santo; Mestrado em Química; Programa de Pós-Graduação em Química; UFES; BR

URL: http://repositorio.ufes.br/handle/10/4694

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O câncer é… (more)

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Made available in DSpace on 2016-08-29T15:35:33Z (GMT). No. of bitstreams: 1 tese_6737_Maicon Delarmelina.pdf: 47315 bytes, checksum: 71d6ef49e51bffadf876359d21c01ed0 (MD5) Previous issue date: 2013-08-30

O câncer é uma das doenças que mais causam temor na sociedade, por ter se tornado um estigma de mortalidade e dor. Estatisticamente, em pesquisa realizada pela Organização Mundial de Saúde (WHO), o câncer é a segunda causa de óbitos no mundo com 13%, matando cerca de 6,0 milhões de pessoas por ano. Acredita-se que em 2015 o câncer seja responsável por 9 milhões de mortes no mundo. Os avanços verificados nas últimas décadas, na área da quimioterapia antineoplásica, têm facilitado consideravelmente a aplicação de outros tipos de tratamento de câncer e permitido maior número de curas. Entretanto, muitos tipos de câncer são intrinsecamente resistentes a quimioterápicos, enquanto outros inicialmente respondem ao tratamento, porém adquirem resistência aos fármacos. A resistência múltipla ao fármaco (MDR), o quadro mais grave, ocorre quando culturas de células in vitro e in vivo mostram resistência simultânea a diferentes fármacos. Portanto, apesar do grande número de compostos que compõem o arsenal quimioterápico de combate ao câncer, o problema de resistência requer a busca constante por novos fármacos eficazes no combate ao câncer, doença que afeta milhões de pessoas. Em estudos farmacológicos com diversas quinonas foi evidenciado que esta classe de substância mostram variadas atividades farmacodinâmicas, dentre elas, as propriedades citotóxicas e inibidoras de sistemas celulares reparadores, processos nos quais atuam de diferentes formas. Como exemplo, destaca-se o estresse oxidativo que provocam ao induzirem a formação deletéria endógena de espécies bioativas derivadas do oxigênio (ROS). Outra atividade marcante destas substâncias, descoberta recentemente, é a inibição da enzima topoisomerase II, ação que provoca o desencadeamento da apoptose celular. Neste trabalho foram sintetizados em rendimentos que variaram de 52 a 89% onze derivados 1,4-naftoquinônicos contendo grupos oxigenados, nitrogenados e sulfurados nas posições 2 e/ou 3 do núcleo naftoquinônico. Posteriormente estes compostos tiveram as suas citotoxidades avaliadas nas linhagens de câncer humano de pulmão (H460), mama triplo-negativo (MDA-MB-231) e ovário (A2780). Os compostos 25f e 44, 25c e 44, e 25g e 44 apresentaram uma significativa atividade anticâncer in vitro para as linhagens de câncer de pulmão H460, mama triplo-negativos MDA-MB-231 e ovário A2780, respectivamente, demostrando um grande potencial como compostos protótipos para o desenvolvimento de novos agentes antineoplásicos. Efetuou-se também estudos de docking dos quatro compostos mais ativos com os alvos terapêuticos PI3K e topoisomerase II. Os estudos mostraram que um possível alvo terapêutico das subtâncias sintetizadas é a enzima topoisomerase II, resultado das interações estabilizadoras observadas no complexo enzima/ligante.

Cancer is one of the most feared disease in…

Advisors/Committee Members: Pinheiro, Sergio, Lacerda Junior, Valdemar, Greco, Sandro José.

Subjects/Keywords: Naftoquinona; Agentes antineoplásicos; Enzimas; Topoisomerase; Docking; 54

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Delarmelina, M. (2013). Síntese, avaliação biológica e docking de novos derivados 2,3-substituídos-1,4-naftoquinônicos contendo nitrogênio, oxigênio e enxofre com atividade anticâncer. (Masters Thesis). Universidade Federal do Espírito Santo; Mestrado em Química; Programa de Pós-Graduação em Química; UFES; BR. Retrieved from http://repositorio.ufes.br/handle/10/4694

Chicago Manual of Style (16^th Edition):

Delarmelina, Maicon. “Síntese, avaliação biológica e docking de novos derivados 2,3-substituídos-1,4-naftoquinônicos contendo nitrogênio, oxigênio e enxofre com atividade anticâncer.” 2013. Masters Thesis, Universidade Federal do Espírito Santo; Mestrado em Química; Programa de Pós-Graduação em Química; UFES; BR. Accessed April 12, 2021. http://repositorio.ufes.br/handle/10/4694.

MLA Handbook (7^th Edition):

Delarmelina, Maicon. “Síntese, avaliação biológica e docking de novos derivados 2,3-substituídos-1,4-naftoquinônicos contendo nitrogênio, oxigênio e enxofre com atividade anticâncer.” 2013. Web. 12 Apr 2021.

Vancouver:

Delarmelina M. Síntese, avaliação biológica e docking de novos derivados 2,3-substituídos-1,4-naftoquinônicos contendo nitrogênio, oxigênio e enxofre com atividade anticâncer. [Internet] [Masters thesis]. Universidade Federal do Espírito Santo; Mestrado em Química; Programa de Pós-Graduação em Química; UFES; BR; 2013. [cited 2021 Apr 12]. Available from: http://repositorio.ufes.br/handle/10/4694.

Council of Science Editors:

Delarmelina M. Síntese, avaliação biológica e docking de novos derivados 2,3-substituídos-1,4-naftoquinônicos contendo nitrogênio, oxigênio e enxofre com atividade anticâncer. [Masters Thesis]. Universidade Federal do Espírito Santo; Mestrado em Química; Programa de Pós-Graduação em Química; UFES; BR; 2013. Available from: http://repositorio.ufes.br/handle/10/4694

28. Eudmar Marcolino de Assis JÃnior. Efeito protetor da silimarina sobre a esteato-hepatite nÃo alcoÃlica experimental induzida por irinotecano.

Degree: 2014, Universidade Federal do CearÃ; Programa de PÃs-GraduaÃÃo em Farmacologia; UFC; BR

URL: http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=12657

► O cÃncer coloretal (CRC) Ã a 3Â neoplasia mais prevalente no mundo. O irinotecano (IRI), fÃrmaco de primeira linha para os tratamentos do CRC e… (more)

▼ O cÃncer coloretal (CRC) Ã a 3Â neoplasia mais prevalente no mundo. O irinotecano (IRI), fÃrmaco de primeira linha para os tratamentos do CRC e sua metÃstase hepÃtica, tem aumentado a sobrevivÃncia dos pacientes. Contudo, seus efeitos colaterais, incluindo a esteato-hepatite nÃo alcoÃlica (NASH), podem limitar o curso do tratamento. Os protocolos baseados em irinotecano foram associados com um aumento no risco de NASH de 3,4 vezes. A silimarina (SIL) tem mostrado ser capaz de prevenir doenÃas do fÃgado gorduroso no contexto clÃnico e em modelos de danos hepÃticos induzidos quimicamente. Assim, nosso objetivo foi estudar o efeito da SIL na NASH induzida pelo IRI, assim como o mecanismo envolvido. MÃtodos e Resultados: Camundongos Swiss fÃmeas (n=8-10), foram divididos em 6 grupos e injetados com salina (SAL 5ml/kg i.p.), IRI (50 mg/kg i.p.), SIL (150 mg/kg v.o.) ou IRI (50 mg/kg i.p.) + SIL (SIL 1,5, 15, 150 mg/kg v.o.) 3x/semana/7 semanas. Amostras de sangue foram coletadas na sÃtima semana para determinar a concentraÃÃo sÃrica das enzimas hepÃticas ALT e AST (U/L). Animais foram mortos para a coleta do fÃgado para avaliar do dano tecidual (escores de Kleiner), dosagem de lipÃdeos totais (mg/g de tecido), MDA (nmol/g tecido), NPSH (mg de NPSH/g tecido), IL-6 (pg/mg de tecido), IL-10 (pg/mg de proteÃna) e IL-1β (pg/mg de tecido), imunomarcaÃÃo de Ãxido nÃtrico sintase induzida (iNOS), 3-Nitrotirosina (Ntyr), e Receptor Toll Like tipo 4 (TLR4), quantificaÃÃo do fator nuclear kappa B (NFκB) e da α-actina de mÃsculo liso (α-SMA) e expressÃo do gene RSS. ANOVA/Teste de Newman-Keuls ou Kruskal Wallis/ Teste de Dunn foram utilizados para anÃlise estatÃstica. Foram consideradas diferentes amostras onde o nÃvel descritivo era inferior a 5%. O trabalho foi aprovado pelo comitÃ de Ãtica em pesquisa animal sob o nÃmero de protocolo: 21/12. O IRI aumentou de forma significante as transaminases hepÃticas, o infiltrado neutrofÃlico, o acÃmo de lipÃdeos, o acÃmulo de MDA, a expressÃo de NTyr, a expressÃo de α-SMA, a expressÃo de NFκB, a expressÃo de IL-1β, a expressÃo de IL-6, a expressÃo de TLR4 e quantificaÃÃo de DNA bacteriano, quando comparados ao grupo SAL. SIL (1,5 mg/kg) melhorou esses parÃmetros, exceto a infiltraÃÃo neutrofÃlica e a quantificaÃÃo do DNA bacteriano quando comparados ao o grupo IRI (P<0,05). Por outro lado, a dose media de SIL (15 mg/kg) foi efetiva apenas no Infiltrado NeutrofÃlico, na expressÃo de NTyr, na expressÃo de NFκB e na expressÃo de IL-6. Adicionalmente, essa dose aumentou a expressÃo hepÃtica de IL-10, a quantificaÃÃo de DNA bacteriano e a expressÃo da α-SMA quando comparados com o grupo IRI (p<0,05). Contudo, a expressÃo de iNOS nÃo foi afetada pelo prÃ-tratamento com SIL (P<0,05) e a maior dose foi ainda mais deletÃria. ConclusÃes: O prÃ-tratamento com SIL previne o dano hepÃtico causado pelo IRI provavelmente atravÃs da mudanÃa da resposta inflamatÃria mediada por receptores TLR4 e citocinas IL-1, IL-6, IL-10 e NFκB. O dano observado no grupo de… Advisors/Committee Members: Roberto CÃsar Pereira Lima JÃnior, Diego Veras Wilke, Marcelo Leite Vieira Costa.

Subjects/Keywords: Topoisomerase Inhibitors; Silymarin; Colorectal Neoplasms; FARMACOLOGIA

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

JÃnior, E. M. d. A. (2014). Efeito protetor da silimarina sobre a esteato-hepatite nÃo alcoÃlica experimental induzida por irinotecano. (Masters Thesis). Universidade Federal do CearÃ; Programa de PÃs-GraduaÃÃo em Farmacologia; UFC; BR. Retrieved from http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=12657

Chicago Manual of Style (16^th Edition):

JÃnior, Eudmar Marcolino de Assis. “Efeito protetor da silimarina sobre a esteato-hepatite nÃo alcoÃlica experimental induzida por irinotecano.” 2014. Masters Thesis, Universidade Federal do CearÃ; Programa de PÃs-GraduaÃÃo em Farmacologia; UFC; BR. Accessed April 12, 2021. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=12657.

MLA Handbook (7^th Edition):

JÃnior, Eudmar Marcolino de Assis. “Efeito protetor da silimarina sobre a esteato-hepatite nÃo alcoÃlica experimental induzida por irinotecano.” 2014. Web. 12 Apr 2021.

Vancouver:

JÃnior EMdA. Efeito protetor da silimarina sobre a esteato-hepatite nÃo alcoÃlica experimental induzida por irinotecano. [Internet] [Masters thesis]. Universidade Federal do CearÃ; Programa de PÃs-GraduaÃÃo em Farmacologia; UFC; BR; 2014. [cited 2021 Apr 12]. Available from: http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=12657.

Council of Science Editors:

JÃnior EMdA. Efeito protetor da silimarina sobre a esteato-hepatite nÃo alcoÃlica experimental induzida por irinotecano. [Masters Thesis]. Universidade Federal do CearÃ; Programa de PÃs-GraduaÃÃo em Farmacologia; UFC; BR; 2014. Available from: http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=12657

Rutgers University

29. Feng, Wei. Structure-activity studies of novel noncamptothecin topoisomerase I-targeting agents.

Degree: PhD, Medicinal Chemistry, 2008, Rutgers University

URL: http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051088

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Topoisomerases are ubiquitous enzymes that participate in processes such as DNA replication, transcription and repair. Two camptothecin derivatives, topotecan (Hycamtin®) and irinotican (CPT-11/ Camptosar®), are… (more)

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Topoisomerases are ubiquitous enzymes that participate in processes such as DNA replication, transcription and repair. Two camptothecin derivatives, topotecan (Hycamtin®) and irinotican (CPT-11/ Camptosar®), are currently used in the clinic as topoisomerse I targeting anticancer agents. Camptothecins can stabilize the enzyme-DNA cleavage complex, leading to DNA damage and ultimately cell death. Despite their unique tumor suppression mechanism, topotecan and irinotican can undergo hydrolysis and inactivation in vivo due to an unstable lactone moiety. In addition, both topotecan and irinotican are substrates for efflux transporters, BCRP and MDR1, which are associated with drug resistance. 8,9-Dimethoxy-5-(2-dimethylaminoethyl)-2,3-methylenedioxy- 5H-dibenzo[c,h][1,6]naphthyridine-6- one (ARC-111) has been identified as exceptionally active TOP1-targeting agent with potent antitumor activity both in vitro and in vivo. Unlike camptothecins, ARC-111 is not a substrate for major efflux transporters, and does not bind to human serum albumin. ARC-111 structurally related analogs, 12-carboxamides of benzo[i]phenathridine and the "reversed lactams" have also exhibited excellent cytotoxicity and potent TOP1 targeting activity. In this dissertation, further insights into structure-activity relationship of ARC-111 and related compounds have been carefully examined. Alteration of both D-ring and side chain of ARC-111 have afforded potent TOP1-targeting agents. Inspired by the success of ARC-111, the design, synthesis and biological activities of other B-ring modified benzo[i]phenathridines have been systematically investigated. In review of possible metabolites of ARC-111, together with the known structure-activity relationships associated with the "reversed lactams", 11-carboxamides and 12-carboxamides of benzo[i]phenathridine, have prompted the examination of α,α-dimethyl substitution on the amino side chain on pharmacologic activity. Efficient synthetic methods associated with these novel non-camptothecin anticancer agents have also been developed. Several agents identified in this study have demonstrated excellent cancer cell cytotoxicity, TOP1 targeting specificity, as well as in vivo antitumor efficacy, comparable as the lead compound, ARC-111.

Advisors/Committee Members: Feng, Wei (author), LaVoie, Edmond (chair), Rice, Joseph (internal member), Kimball, S. David (internal member), Jones, Roger (outside member).

Subjects/Keywords: DNA topoisomerase I

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Feng, W. (2008). Structure-activity studies of novel noncamptothecin topoisomerase I-targeting agents. (Doctoral Dissertation). Rutgers University. Retrieved from http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051088

Chicago Manual of Style (16^th Edition):

Feng, Wei. “Structure-activity studies of novel noncamptothecin topoisomerase I-targeting agents.” 2008. Doctoral Dissertation, Rutgers University. Accessed April 12, 2021. http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051088.

MLA Handbook (7^th Edition):

Feng, Wei. “Structure-activity studies of novel noncamptothecin topoisomerase I-targeting agents.” 2008. Web. 12 Apr 2021.

Vancouver:

Feng W. Structure-activity studies of novel noncamptothecin topoisomerase I-targeting agents. [Internet] [Doctoral dissertation]. Rutgers University; 2008. [cited 2021 Apr 12]. Available from: http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051088.

Council of Science Editors:

Feng W. Structure-activity studies of novel noncamptothecin topoisomerase I-targeting agents. [Doctoral Dissertation]. Rutgers University; 2008. Available from: http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051088

30. Assis Júnior, Eudmar Marcolino de. Efeito protetor da silimarina sobre a esteato-hepatite não alcoólica experimental induzida por irinotecano.

Degree: 2014, Brazil

URL: http://www.repositorio.ufc.br/handle/riufc/9354

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Approved for entry into archive by denise santos([email protected])… (more)

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Made available in DSpace on 2014-10-08T14:01:07Z (GMT). No. of bitstreams: 1 2014_dis_emassisjunior.pdf: 1785225 bytes, checksum: fd28c699a89420b841078e99f342b777 (MD5) Previous issue date: 2014

O câncer coloretal (CRC) é a 3º neoplasia mais prevalente no mundo. O irinotecano (IRI), fármaco de primeira linha para os tratamentos do CRC e sua metástase hepática, tem aumentado a sobrevivência dos pacientes. Contudo, seus efeitos colaterais, incluindo a esteato-hepatite não alcoólica (NASH), podem limitar o curso do tratamento. Os protocolos baseados em irinotecano foram associados com um aumento no risco de NASH de 3,4 vezes. A silimarina (SIL) tem mostrado ser capaz de prevenir doenças do fígado gorduroso no contexto clínico e em modelos de danos hepáticos induzidos quimicamente. Assim, nosso objetivo foi estudar o efeito da SIL na NASH induzida pelo IRI, assim como o mecanismo envolvido. Métodos e Resultados: Camundongos Swiss fêmeas (n=8-10), foram divididos em 6 grupos e injetados com salina (SAL 5ml/kg i.p.), IRI (50 mg/kg i.p.), SIL (150 mg/kg v.o.) ou IRI (50 mg/kg i.p.) + SIL (SIL 1,5, 15, 150 mg/kg v.o.) 3x/semana/7 semanas. Amostras de sangue foram coletadas na sétima semana para determinar a concentração sérica das enzimas hepáticas ALT e AST (U/L). Animais foram mortos para a coleta do fígado para avaliar do dano tecidual (escores de Kleiner), dosagem de lipídeos totais (mg/g de tecido), MDA (nmol/g tecido), NPSH (mg de NPSH/g tecido), IL-6 (pg/mg de tecido), IL-10 (pg/mg de proteína) e IL-1β (pg/mg de tecido), imunomarcação de óxido nítrico sintase induzida (iNOS), 3-Nitrotirosina (Ntyr), e Receptor Toll Like tipo 4 (TLR4), quantificação do fator nuclear kappa B (NFκB) e da α-actina de músculo liso (α-SMA) e expressão do gene RSS. ANOVA/Teste de Newman-Keuls ou Kruskal Wallis/ Teste de Dunn foram utilizados para análise estatística. Foram consideradas diferentes amostras onde o nível descritivo era inferior a 5%. O trabalho foi aprovado pelo comitê de ética em pesquisa animal sob o número de protocolo: 21/12. O IRI aumentou de forma significante as transaminases hepáticas, o infiltrado neutrofílico, o acúmo de lipídeos, o acúmulo de MDA, a expressão de NTyr, a expressão de α-SMA, a expressão de NFκB, a expressão de IL-1β, a expressão de IL-6, a expressão de TLR4 e quantificação de DNA bacteriano, quando comparados ao grupo SAL. SIL (1,5 mg/kg) melhorou esses parâmetros, exceto a infiltração neutrofílica e a quantificação do DNA bacteriano quando comparados ao o grupo IRI (P<0,05). Por outro lado, a dose media de SIL (15 mg/kg) foi efetiva apenas no Infiltrado Neutrofílico, na expressão de NTyr, na…

Advisors/Committee Members: Lima Júnior, Roberto César Pereira.

Subjects/Keywords: Inibidores da Topoisomerase; Silimarina; Neoplasias Colorretais

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Assis Júnior, E. M. d. (2014). Efeito protetor da silimarina sobre a esteato-hepatite não alcoólica experimental induzida por irinotecano. (Masters Thesis). Brazil. Retrieved from http://www.repositorio.ufc.br/handle/riufc/9354

Chicago Manual of Style (16^th Edition):

Assis Júnior, Eudmar Marcolino de. “Efeito protetor da silimarina sobre a esteato-hepatite não alcoólica experimental induzida por irinotecano.” 2014. Masters Thesis, Brazil. Accessed April 12, 2021. http://www.repositorio.ufc.br/handle/riufc/9354.

MLA Handbook (7^th Edition):

Assis Júnior, Eudmar Marcolino de. “Efeito protetor da silimarina sobre a esteato-hepatite não alcoólica experimental induzida por irinotecano.” 2014. Web. 12 Apr 2021.

Vancouver:

Assis Júnior EMd. Efeito protetor da silimarina sobre a esteato-hepatite não alcoólica experimental induzida por irinotecano. [Internet] [Masters thesis]. Brazil; 2014. [cited 2021 Apr 12]. Available from: http://www.repositorio.ufc.br/handle/riufc/9354.

Council of Science Editors:

Assis Júnior EMd. Efeito protetor da silimarina sobre a esteato-hepatite não alcoólica experimental induzida por irinotecano. [Masters Thesis]. Brazil; 2014. Available from: http://www.repositorio.ufc.br/handle/riufc/9354

Open Access Theses and Dissertations